Methods and compositions for treating recurrent cancer

ABSTRACT

The present invention provides methods of treating recurrent cancer (such as recurrent ovarian, peritoneal, or fallopian tube cancer) in an individual, comprising administering to the individual an effective amount of a composition (such as Nab-paclitaxel or Abraxane®) comprising nanoparticles comprising a taxane and a carrier protein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of the U.S. ProvisionalPatent Application No. 60/932,750 filed on Jun. 1, 2007, the content ofwhich is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to methods and compositions for thetreatment of recurrent cancer, particularly recurrent ovarian cancer,comprising the administration of compositions comprising nanoparticlescomprising taxane and a carrier protein (such as albumin).

BACKGROUND

Ovarian cancer forms in tissues of an ovary (one of a pair of femalereproductive glands in which the ova, or eggs, are formed). Most ovariancancers are either ovarian epithelial carcinomas (cancer that begins inthe cells on the surface of the ovary) or malignant germ cell tumors(cancer that begins in egg cells). According to the National CancerInstitute, ovarian cancer is the seventh most common cancer, with anestimated 20,180 new cases in 2006, but is the fourth most deadly, withan estimated 15,310 deaths in 2006.

A possible genetic contribution to ovarian cancer risk is indicated bythe increased incidence of this cancer among women with a familyhistory, and by the observation of rare families in which multiplefamily members are affected with ovarian cancer, in a pattern compatiblewith autosomal dominant inheritance of cancer susceptibility. Formalstudies of families (linkage analysis) have subsequently proven theexistence of autosomal dominant predispositions to ovarian cancer andhave led to the identification of several highly penetrant genes as thecause of inherited cancer risk in many cancer-prone families. Mutationsin these genes are rare in the general population and are estimated toaccount for no more than 5% to 10% of ovarian cancer cases overall.

Although reproductive, demographic, and lifestyle factors affect risk ofovarian cancer, the single greatest ovarian cancer risk factor is afamily history of the disease. A large meta-analysis of 15 publishedstudies estimated an odds ratio (OR) of 3.1 for the risk of ovariancancer associated with at least one first-degree relative with ovariancancer.

Despite recent improvements, initial or first-line chemotherapy fails toproduce a remission in more than 70% of patients with ovarian cancer.Furthermore, approximately 40-50% of the women who do achieve aremission after first-line chemotherapy will experience a recurrence ofcancer within 3 years. Patients with recurrent ovarian, peritoneal, orfallopian tube cancer generally have a poor outcome with currenttherapies. There is a need for effective treatment method for patientswith recurrent ovarian cancers. Preferably, the treatments overcome theshortcomings of current drug and transplant treatments, such ashypersensitivity reactions due to the solvent/surfactant in which drugsare dissolved.

Many anti-proliferative agents are dissolved in a solvent/surfactantwhich produces hypersensitivity reactions. Great efforts have beeninvested on the development of water soluble prodrugs and derivatives ofanti-proliferative agents with higher hydrophilic groups to enhancewater solubility and thus obviate the need for potentially toxicsolvents/surfactants. Another approach to address the problem associatedwith the poor water solubility of anti-proliferative agents is thedevelopment of various formulations such as nanoparticles, oil-in-wateremulsions, and liposomes. For example, Abraxane® is a nanoparticlecomposition of paclitaxel and albumin. Nanoparticle compositions ofsubstantially poorly water soluble drugs and uses thereof have beendisclosed, for example, in U.S. Pat. Nos. 5,916,596; 6,096,331;6,749,868; and 6,537,579; U.S. Patent Appln. Pub. No. US20030199425; andPCT Application Pub. Nos. WO98/14174, WO99/00113, WO07/027,941 andWO07/027,819. Administration of Abraxane® to a patient with recurrentovarian cancer is described in Mida et al., Gynecologic Oncology,100:437-438 (2006).

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein are hereby incorporatedherein by reference in their entirety.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods for the treatment of a recurrentcancer (such as a recurrent gynecological cancer) by administering acomposition comprising nanoparticles comprising a taxane and a carrierprotein (hereinafter referred to as “taxane nanoparticle composition”).In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin). In someembodiments, the recurrent cancer (such as a recurrent gynecologicalcancer, for example recurrent ovarian, peritoneal, or fallopian tubecancer) is platinum sensitive. In some embodiments, the recurrent cancer(such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) is platinum resistant. Insome embodiments, the recurrent cancer is a recurrent lung cancer.

In some embodiments, the recurrent cancer is a recurrent gynecologicalcancer. In some embodiments, the recurrent gynecological cancer is arecurrent ovarian cancer (such as a recurrent epithelial ovariancancer). In some embodiments, the recurrent gynecological cancer is arecurrent peritoneal cancer. In some embodiments, the recurrentgynecological cancer is a recurrent fallopian tube cancer (including forexample papillary serous adenocarcinomas, sarcomas, and transitionalcell carcinomas). Other recurrent gynecological cancers such asrecurrent malignant mixed mullerian tumor and serous endo can also betreated.

In some embodiments, the individual is a woman who is about 40 to about85 years old, including for example about 60 to about 70 years old. Insome embodiments, the individual has an Eastern Cooperative OncologyGroup (ECOG) performance status of 0-2 (such as any of 0, 1, or 2) priorto the administration of the taxane nanoparticle composition. In someembodiments, the individual has received a prior cancer therapy (such aschemotherapy) and has a treatment free interval for more than about anyof 3, 6, or 9 months since the completion of prior chemotherapy. In someembodiments, the individual has received a prior cancer therapy (such aschemotherapy) and has a treatment free interval for more than about anyof 12, 18, 24, 36, or 48 months since the completion of priorchemotherapy. In some embodiments, the prior chemotherapy has adifferent mechanism of action than that of the taxane. In someembodiments, the individual has only been treated with platinum-basedagent(s) prior to the administration of the taxane nanoparticlecomposition. In some embodiments, the individual has only been treatedwith one dosing regime prior to the administration of the taxanenanoparticle composition. In some embodiments, the individual has notpreviously been treated with a taxane-based therapy.

In some embodiments, the individual has received a prior cancer therapy(such as chemotherapy) and has a treatment free interval for more thanabout any of 3, 6, or 9 months prior to the initiation of the methodsdescribed herein. In some embodiments, the individual has received aprior cancer therapy (such as chemotherapy) and has a treatment freeinterval for more than about any of 12, 18, 24, 36, or 48 months priorto the initiation of the methods described herein. In some embodiments,the individual does not show a symptom of hypersensitivity (such asneuropathy) prior to the initiation of the methods described herein(such as within 12, 9, 6, 5, 4, 3, 2, or 1 month prior to the initiationof the methods described herein). In some embodiments, the individualdoes not show a symptom of hypersensitivity throughout the treatmentperiod with methods described herein. In some embodiments, theindividual does not show a symptom of hypersensitivity upon completionof the treatment with methods described herein.

In some embodiments when the method is directed to treatment of arecurrent ovarian, peritoneal, or fallopian tube cancer, the individualmay be confirmed of having an ovarian, peritoneal, or fallopian tubecancer histologically or cytologically. In some embodiments, theindividual is determined to have an ovarian, peritoneal, or fallopiantube cancer based on RECIST (Response Evaluation Criteria in SolidTumors). In some embodiments, the individual has an elevated blood levelof Cancer Antigen 125 (CA-125, for example a CA-125 level of more thanabout 40, 50, 60, 70, 80, or 90 units/ml, or about 2×, 3×, 4×, or moreof that of the upper limit of a normal CA-125 level). In someembodiments, the individual has an altered level of a marker that isindicative of an ovarian, peritoneal, or fallopian tube cancer.

In some embodiments, the individual satisfies at least two of thecriteria described above. For example, in some embodiments, theindividual has a measurable disease by RECIST and an elevated bloodlevel of CA-125. In some embodiments, the individual is confirmed ofhaving an ovarian cancer histologically or cytologically and has onlybeen treated with platinum-based agent(s) prior to administration of thenanoparticle compositions described above. In some embodiments, theindividual satisfies at least any of two, three, four, five, or morecriteria described above. In some embodiments, the individual satisfiesall criteria described above.

In some embodiments, the recurrent cancer (such as recurrent ovariancancer) is platinum-sensitive. For example, in some embodiments, theindividual has received prior platinum-based chemotherapy and has atreatment-free interval for more than about any of 3, 6, or 9 monthssince the completion of the platinum-based chemotherapy. In someembodiments, the individual has received prior platinum-basedchemotherapy and has a treatment-free interval for more than about anyof 12, 18, 24, 36, or 48 months since the completion of theplatinum-based chemotherapy. Platinum-based chemotherapy includes, butis not limited to, treatment with carboplatin, cisplatin, andoxaliplatin. In some embodiments, the platinum-based chemotherapy istreatment with carboplatin.

The methods described herein comprise administering to the individual aneffective amount of a composition comprising nanoparticles comprising ataxane (such as paclitaxel) and a carrier protein (such as albumin). Insome embodiments, the taxane nanoparticle composition is administered inconjunction with another chemotherapeutic agent (such as aplatinum-based agent). For example, the taxane nanoparticle compositionand the other chemotherapeutic agent (such as a platinum-based agent)can be administered sequentially, simultaneously, or concurrently. Insome embodiments, the other chemotherapeutic agent (such asplatinum-based agent) is administered in the same composition as thenanoparticles comprising taxane and carrier protein. The otherchemotherapeutic agent (such as platinum-based agent) can also beformulated into a nanoparticle composition as described herein.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), and b) an effectiveamount of a platinum-based agent. In some embodiments, there is provideda method of treating a recurrent cancer (such as a recurrentgynecological cancer, for example recurrent ovarian, peritoneal, orfallopian tube cancer) in an individual, comprising administering to theindividual a) an effective amount of a composition comprisingnanoparticles comprising paclitaxel and an albumin (such as Abraxane®),and b) an effective amount of a platinum-based agent. Suitableplatinum-based agents include, but are not limited to, carboplatin,cisplatin, and oxaliplatin. In some embodiments, the platinum-basedagent is carboplatin. In some embodiments, the taxane nanoparticlecomposition and the platinum-based agent are administeredsimultaneously. In some embodiments, the taxane nanoparticle compositionand the platinum-based agent are administered sequentially. In someembodiments, the taxane nanoparticle composition and the platinum-basedagent is administered concurrently.

In some embodiments, there is provided a method of treating a recurrentovarian cancer in an individual, comprising administering to theindividual: a) an effective amount of a composition comprisingnanoparticles comprising a taxane (such as paclitaxel) and a carrierprotein (such as albumin), and b) an effective amount of aplatinum-based agent. In some embodiments, there is provided a method oftreating a primary peritoneal cancer in an individual, comprisingadministering to the individual: a) an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), and b) an effective amount of aplatinum-based agent.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), and b) an effectiveamount of a platinum-based agent, wherein the taxane nanoparticlecomposition and the platinum-based agent are administered concurrently.In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a paclitaxel and analbumin (such as Abraxane®), and b) an effective amount of aplatinum-based agent, wherein the paclitaxel nanoparticle compositionand the platinum-based agent are administered concurrently.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering (for example intravenously orintraperitoneally) to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a paclitaxel and analbumin (such as Abraxane®), wherein the amount of the paclitaxel in thecomposition is at least about 40 mg/m² (including for example about anyof 50 mg/m², 60 mg/m², 70 mg/m², 80 mg/m², 90 mg/m², 100 mg/m², 150mg/m², or 200 mg/m²); b) an effective amount of a platinum-based agent(such as the platinum-based agent at the amount of AUC3, AUC4, or AUC6),wherein the taxane nanoparticle composition and the platinum-based agentare administered concurrently. In some embodiments, the method comprisesadministering a composition comprising nanoparticles comprisingpaclitaxel and an albumin (such as Abraxane®) at about 100 mg/m², threeout of four weeks, and a platinum-based agent (such as carboplatin) AUC6every four weeks in the same treatment cycle. In some embodiments, themethod comprises administering a composition comprising nanoparticlescomprising paclitaxel and an albumin (such as Abraxane®) at about 100mg/m², three out of four weeks, and a platinum-based agent (such ascarboplatin) AUC5 every four weeks in the same treatment cycle. In someembodiments, the method comprises intravenously administering acomposition comprising nanoparticles comprising paclitaxel and analbumin (such as Abraxane®) at about 100 mg/m², three out of four weeks,and intravenously administering a platinum-based agent (such ascarboplatin) AUC5 every four weeks in the same treatment cycle. In someembodiments, the individual is treated with at least any of about one,two, three, four, five, six, seven, eight, or more such treatmentcycles.

In some embodiments, there is provided a method of treating recurrentovarian cancer, comprising intravenously administering a compositioncomprising nanoparticles comprising paclitaxel and an albumin (such asAbraxane®) at about 100 mg/m², three out of four weeks, andintravenously administering a platinum-based agent (such as carboplatin)AUC5 (or AUC6) every four weeks in the same treatment cycle. In someembodiments, there is provided a method of treating primary peritonealcancer, comprising intravenously administering a composition comprisingnanoparticles comprising paclitaxel and an albumin (such as Abraxane®)at about 100 mg/m², three out of four weeks, and intravenouslyadministering a platinum-based agent (such as carboplatin) AUC5 (orAUC6) every four weeks in the same treatment cycle. In some embodiments,the individual is treated with at least any of about one, two, three,four, five, six, seven, eight, or more such treatment cycles.

In some embodiments, the taxane nanoparticle composition is notadministered in conjunction with a platinum-based agent, that is, thetaxane nanoparticle composition is either administered in a monotherapydosing regime or administered in conjunction with a chemotherapeuticagent other than a platinum-based agent. In some embodiments, aplatinum-based agent is not administered to the individual during thetime period in which the individual is receiving one or more doses ofthe taxane nanoparticle composition. In some embodiments, the individualis not treated with a platinum-based agent concurrently with theadministration of the taxane nanoparticle composition.

In some embodiments, the taxane nanoparticle composition can beadministered alone, that is, the taxane nanoparticle is administered ina monotherapy dosing regime. For example, in some embodiments, theamount of the taxane nanoparticle composition administered alone issufficient to result in a complete response in the individual. In someembodiments, the amount of the taxane nanoparticle compositionadministered alone is sufficient to result in a partial response in theindividual. In some embodiments, the amount of the taxane nanoparticlecomposition administered alone is sufficient to produce an overallresponse rate of more than about any of 40%, 50%, 60%, or 64% among apopulation of individuals treated with the taxane nanoparticlecomposition. In some embodiments, the amount of taxane nanoparticlecomposition administered alone is sufficient to produce clinical benefitof more than about any of 50%, 60%, 70%, or 77% among a population ofindividuals treated with the taxane nanoparticle composition.

The taxane nanoparticle compositions described herein comprisenanoparticles comprising taxane (such as paclitaxel) and a carrierprotein. In some embodiments, the taxane is paclitaxel, docetaxel,ortataxel, or IDN5390. In some embodiments, the carrier protein isalbumin, such as human serum albumin. In some embodiments, the weightratio of the carrier protein to the taxane in the taxane nanoparticlecomposition is less than about 18:1 (including for example less thanabout any of 15:1, 12:1, 10:1, such as 9:1).

In some embodiments, the nanoparticles comprise the taxane coated with acoating comprising the carrier protein (such as albumin). In someembodiments, the coating consists essentially of or consists of thecarrier protein. In some embodiments, at least a portion of the carrierprotein in the nanoparticle portion of the taxane nanoparticlecomposition is crosslinked (for example crosslinked by disulfide bonds).In some embodiments, the nanoparticles of the composition comprise atleast 5% (including for example at least any of 10%, 15%, 20%, or 25%)of carrier protein that is cross-linked.

In some embodiments, the average or mean diameter of the nanoparticlesin the composition is no greater than about 200 nm. In some embodiments,the average or mean diameter of the particles is between about 20 nm toabout 400 nm (such as about 40 nm to about 200 nm). In some embodiments,the nanoparticles are sterile-filterable. In some embodiments, thetaxane in the nanoparticles is amorphous. In some embodiments, thenanoparticles are substantially free of polymeric core materials. Insome embodiments, the nanoparticles comprise a core of taxane that issubstantially free of polymeric materials (such as polymertic matrix).In some embodiments, the nanoparticles in the composition have a solidcore. In some embodiments, the nanoparticles in the composition have acore that is not aqueous (i.e., other than aqueous core). In someembodiments, the nanoparticles of the composition are substantially freeof lipids. In some embodiments, the nanoparticles of the composition arefree of lipids.

In some embodiments, the composition comprises more than about 50% (forexample more than about any of 60%, 70%, 80%, 90%, or 95%) of the taxanein nanoparticle form. In some embodiments, the weight percentage of thetaxane in the nanoparticle portion of the taxane nanoparticlecomposition is at least about any of 50%, 60%, 70%, 80%, 90%, or 95% ofthe total weight of the nanoparticle portion of the composition.

In some embodiments, the composition is administered at least about anyof once every three weeks, once every two weeks, once a week, twice aweek, three times a week, four times a week, five times a week, sixtimes a week, or daily. Other exemplary dosing frequencies include, butare not limited to, weekly, two out of three weeks; weekly, three out offour weeks; and weekly, four out of five weeks. In some embodiments, thecomposition is administered (with or without breaks in administrationcycles) for at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,or more month(s).

In some embodiments, the composition is administered via any ofintravenous, intraperitoneal, oral or inhalational routes. In someembodiments, the nanoparticle composition is administered withpremedication. In some embodiments, the nanoparticle composition isadministered without premedication.

The dose of the taxane in the nanoparticle composition will depend onthe type of cancer to be treated, the severity and course of the cancer,the individual's clinical history, and the discretion of the attendingphysician. Suitable dosages of the taxane in the taxane nanoparticlecompositions include, but are not limited to, about any of 50 mg/m², 60mg/m², 75 mg/m², 80 mg/m², 90 mg/m², 100 mg/m², 120 mg/m², 125 mg/m²,150 mg/m², 160 mg/m², 180 mg/m², 200 mg/m², 210 mg/m², 220 mg/m², 230mg/m², 240 mg/m², 260 mg/m², and 300 mg/m². Exemplary dosing schedulesfor the administration of the taxane nanoparticle composition (such aspaclitaxel/albumin nanoparticle composition, for example Abraxane®)include, but are not limited to, 260 mg/m², every three weeks; 60-150mg/m², weekly, without break, and 60-150 mg/m², weekly, three out offour weeks. In addition, the taxane can be administered by following ametronomic dosing regime described herein. In some embodiments, themethod comprises administering Abraxane® at 260 mg/m² by 30 minutes IVinfusion every three weeks.

Also provided herein are compositions, kits and unit dosage forms thatare suitable for methods described herein. For example, in someembodiments, there is provided a composition for use in the treatment ofa recurrent cancer (such as recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, and fallopian tube cancer), wherein thecomposition comprises nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin). In someembodiments, there is provided a composition for use in decreasing oneor more symptoms resulting from a recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer), wherein the composition comprises nanoparticlescomprising a taxane (such as paclitaxel) and a carrier protein (such asalbumin). In some embodiments, there is provided a composition for usein the treatment of a recurrent cancer (such as recurrent gynecologicalcancer for example recurrent ovarian, peritoneal, and fallopian tubecancer) in conjunction with a platinum-based agent, wherein thecomposition comprises nanoparticles comprising a taxane (such aspaclitaxel), wherein the composition comprises nanoparticles comprisinga taxane (such as paclitaxel) and a carrier protein (such as albumin).In some embodiments, there is provided a composition for use indecreasing one or more symptoms resulting from a recurrent cancer (suchas recurrent gynecological cancer for example recurrent ovarian,peritoneal, and fallopian tube cancer) in conjunction with aplatinum-based agent, wherein the composition comprises nanoparticlescomprising a taxane (such as paclitaxel) and a carrier protein (such asalbumin).

These and other aspects and advantages of the present invention willbecome apparent from the subsequent detailed description and theappended claims. It is to be understood that one, some, or all of theproperties of the various embodiments described herein may be combinedto form other embodiments of the present invention.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 a shows overall survival among patients plotted in terms ofmonths (x-axis) to proportion of survival (y-axis).

FIG. 1 b shows progression free survival among patients plotted in termsof months (x-axis) to proportion not progressed (y-axis).

FIG. 2 shows a comparison of plasma level of paclitaxel whenNab-paclitaxel is administered intraperitoneally or intravenously(log-log).

FIG. 3 shows a comparison of plasma level of paclitaxel whenNab-paclitaxel is administered intraperitoneally or intravenously(log-linear).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for the treatment of a recurrentcancer (such as recurrent gynecological cancer) comprising administeringto the individual an effective amount of a composition comprisingnanoparticles comprising a taxane (such as paclitaxel) and a carrierprotein (such as albumin). Specifically, we have shown that acomposition comprising nanoparticles comprising a taxane and a carrierprotein (hereinafter designated as a “taxane nanoparticle composition”),particularly, a composition comprising nanoparticles comprisingpaclitaxel and albumin, more particularly, a composition comprisingnanoparticles albumin bound paclitaxel (“Nab-paclitaxel”), was veryactive as a single agent or in combination with a platinum-based agent(carboplatin) in patients with platinum sensitive recurrentgynecological cancer, including recurrent ovarian, peritoneal, orfallopian tube cancer. The overall response rate for the treatment was64% and the clinical benefit rate was 77%. Complete response wasattained in about 70% patients treated with Abraxane® and carboplatin.This demonstrates that a taxane nanoparticle composition is particularlysuitable (either as a single agent or in combination with aplatinum-based agent) for treating platinum-sensitive recurrent cancer,particularly recurrent gynecological cancer.

Accordingly, the present invention in one aspect provides a method oftreating a platinum-sensitive recurrent cancer comprising administeringto the individual an effective amount of a composition (such asNab-paclitaxel or Abraxane®) comprising nanoparticles comprising ataxane (such as paclitaxel) and a carrier protein (such as albumin). Inanother aspect, there is provided a method of treating a recurrentovarian cancer (such as platinum-sensitive recurrent ovarian cancer)comprising administering to the individual an effective amount of acomposition (such as Nab-paclitaxel or Abraxane®) comprisingnanoparticles comprising a taxane (such as paclitaxel) and a carrierprotein (such as albumin).

DEFINITIONS

As used herein, “the composition” or “compositions” includes and isapplicable to compositions of the invention. The invention also providespharmaceutical compositions comprising the components described herein.

Reference to “taxane” herein applies to a taxane or its derivatives andaccordingly the invention contemplates and includes all thesevariations. Reference to “taxane” is to simplify the description and isexemplary. Taxanes include, but are not limited to, compounds that arestructurally similar to or are in the same general chemical class suchas paclitaxel (i.e., taxol), docetaxel (i.e., taxotere), or ortataxel,and pharmaceutically acceptable salts, derivatives, or analogs ofpaclitaxel, docetaxel, and ortataxel. Taxanes are antimicrobial agentsthat inhibit cell replication by promoting the assembly andstabilization of microtubule from tubulin dimers

Unless clearly indicated otherwise, “an individual” as used hereinrefers to human.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: decreasing one or moresymptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), delay or slowing the progression of thedisease, ameliorating the disease state, decreasing the dose of one ormore other medications required to treat the disease, increasing thequality of life, and/or prolonging survival (including overall survivaland progression free survival. In some embodiments, the compositionreduces the severity of one or more symptoms associated with cancer byat least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%,or 100% compared to the corresponding symptom in the same subject priorto treatment or compared to the corresponding symptom in other subjectsnot receiving the composition. Also encompassed by “treatment” is areduction of pathological consequence of cancer. The methods of theinvention contemplate any one or more of these aspects of treatment.

As used herein, “delaying” the development of cancer means to defer,hinder, slow, retard, stabilize, and/or postpone development of thedisease. This delay can be of varying lengths of time, depending on thehistory of the disease and/or individual being treated. As is evident toone skilled in the art, a sufficient or significant delay can, ineffect, encompass prevention, in that the individual does not developthe disease. A method that “delays” development of cancer is a methodthat reduces probability of disease development in a given time frameand/or reduces the extent of the disease in a given time frame, whencompared to not using the method. Such comparisons are typically basedon clinical studies, using a statistically significant number ofsubjects. Cancer development can be detectable using standard methods,such as routine physical exams or x-ray. Development may also refer todisease progression that may be initially undetectable and includesoccurrence and onset.

“Adjuvant setting” refers to a clinical setting in which an individualhas had a history of ovarian cancer, and generally (but not necessarily)been responsive to therapy, which includes, but is not limited to,surgery (e.g., surgical resection), radiotherapy, and chemotherapy.However, because of their history of the cancer, these individuals areconsidered at risk of development of the disease. Treatment oradministration in the “adjuvant setting” refers to a subsequent mode oftreatment. The degree of risk (i.e., when an individual in the adjuvantsetting is considered as “high risk” or “low risk”) depends upon severalfactors, most usually the extent of disease when first treated.

“Neoadjuvant setting” refers to a clinical setting in which the methodis be carried out before the primary/definitive therapy.

As used herein, an “at risk” individual is an individual who is at riskof developing cancer. An individual “at risk” may or may not havedetectable disease, and may or may not have displayed detectable diseaseprior to the treatment methods described herein. “At risk” denotes thatan individual has one or more so-called risk factors, which aremeasurable parameters that correlate with development of cancer, whichare described herein. An individual having one or more of these riskfactors has a higher probability of developing cancer than an individualwithout these risk factor(s).

As used herein, by “pharmaceutically active compound” is meant achemical compound that induces a desired effect, e.g., treating,stabilizing, preventing, and/or delaying cancer.

As used herein, by “combination therapy” is meant a first therapy thatincludes nanoparticles comprising nanoparticles comprising a taxane(e.g. paclitaxel) and a carrier protein in conjunction with a secondtherapy (e.g., surgery or a therapeutic agent) useful for treating,stabilizing, preventing, and/or delaying cancer. Administration in“conjunction with” another compound includes administration in the sameor different composition(s), either sequentially, simultaneously, orcontinuously. In some embodiments, the combination therapy optionallyincludes one or more pharmaceutically acceptable carriers or excipients,non-pharmaceutically active compounds, and/or inert substances.

The term “effective amount” refers to an amount of a drug effective totreat cancer in the patient. The effective amount of the drug may reducethe number of cancer cells; reduce the tumor size; inhibit (i.e., slowto some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. The effectiveamount may extend progression free survival (e.g. as measured byResponse Evaluation Criteria for Solid Tumors, RECIST, or CA-125changes), result in an objective response (including a partial responseor a complete response), increase overall survival time, and/or improveone or more symptoms of cancer (e.g. as assessed by FOSI).

As is understood in the art, an “effective amount” may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and ananoparticle composition (e.g., a composition including a taxane (e.g.,paclitaxel) and a carrier protein) may be considered to be given in aneffective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved.

In some embodiments, the amount of the composition is an amountsufficient to decrease the size of a tumor, decrease the number ofcancer cells, or decrease the growth rate of a tumor by at least aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% comparedto the corresponding tumor size, number of cancer cells, or tumor growthrate in the same subject prior to treatment or compared to thecorresponding activity in other subjects not receiving the treatment.Standard methods can be used to measure the magnitude of this effect,such as in vitro assays with purified enzyme, cell-based assays, animalmodels, or human testing.

The term “proteins” refers to polypeptides or polymers of amino acids ofany length (including full length or fragments), which may be linear orbranched, comprise modified amino acids, and/or be interrupted bynon-amino acids. The term also encompasses an amino acid polymer thathas been modified naturally or by intervention, including, for example,disulfide bond formation, glycosylation, lipidation, acetylation,phosphorylation, or any other manipulation or modification. Alsoincluded within this term are, for example, polypeptides containing oneor more analogs of an amino acid (including, for example, unnaturalamino acids, etc.), as well as other modifications known in the art. Theproteins described herein may be naturally-occurring, i.e., obtained orderived from a natural source (e.g., blood) or synthesized (e.g.,chemically synthesized or by synthesized by recombinant DNA techniques).Exemplary carrier proteins are described herein.

The term “antimicrobial agent” used herein refers to an agent that iscapable of inhibiting (e.g., delaying, reducing, slowing, and/orpreventing) the growth of one or more microorganisms. Significantmicrobial growth can be measured or indicated by a number of ways knownin the art, such as one or more of the following: (i) microbial growthin a composition that is enough to cause one or more adverse effects toan individual when the composition is administered to the individual;(ii) more than about 10-fold increase in microbial growth over a certainperiod of time (for example over a 24 hour period) upon extrinsiccontamination (e.g., exposure to 10-10³ colony forming units at atemperature in the range of 20 to 25° C.). Other indicia of significantmicrobial growth are described in U.S. Patent Application PublicationNo. US20070117744 (U.S. Ser. No. 11/514,030, filed Aug. 30, 2006), whichis hereby incorporated by reference in its entirety.

“Sugar” as used herein includes, but is not limited to, monosaccharides,disaccharides, polysaccharides, and derivatives or modificationsthereof. Suitable sugars for compositions described herein include, forexample, mannitol, sucrose, fructose, lactose, maltose, and trehalose.

As used herein, by “pharmaceutically acceptable” or “pharmacologicallycompatible” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Survival” refers to the patient remaining alive, and includes overallsurvival as well as progression free survival.

“Overall survival” refers to the patient remaining alive for a definedperiod of time, such as 1 year, 5 years, etc. from the time of diagnosisor treatment.

“Progression free survival” refers to the patient remaining alive,without the cancer progressing or getting worse.

By “prolonging survival” is meant increasing overall or progression freesurvival in a treated patient relative to an untreated patient (e.g.relative to a patient not treated with a taxane nanoparticlecomposition).

As used herein, reference to “not” a value or parameter generally meansand describes “other than” a value or parameter. For example, if ataxane is not administered, it means an agent other than a taxane isadministered.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.’

As used herein and in the appended claims, the singular forms “a,” “or,”and “the” include plural referents unless the context clearly dictatesotherwise. It is understood that aspects and variations of the inventiondescribed herein include “consisting” and/or “consisting essentially of”aspects and variations.

Methods of the Present Invention

The present invention provides methods for the treatment of a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) by administering acomposition comprising nanoparticles comprising a taxane and a carrierprotein. In some embodiments, there is provided a method of treating arecurrent cancer in an individual, comprising administering to theindividual an effective amount of a composition comprising nanoparticlescomprising a taxane and a carrier protein. In some embodiments, therecurrent cancer is platinum sensitive. In some embodiments, therecurrent cancer is platinum resistant. In some embodiments, therecurrent cancer is any of recurrent ovarian cancer, recurrentperitoneal cancer, recurrent fallopian tube cancer, recurrent malignantmixed mullerian tumor, and serous endo.

In some embodiments, there is provided a method of treating a recurrentovarian, peritoneal, or fallopian tube cancer in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane and a carrierprotein. In some embodiments, there is provided a method of treating aplatinum-sensitive recurrent ovarian, peritoneal, or fallopian tubecancer in an individual, comprising administering to the individual aneffective amount of a composition comprising nanoparticles comprising ataxane and a carrier protein. In some embodiments, the recurrent canceris a recurrent ovarian cancer (such as a recurrent epithelial ovariancancer). In some embodiments, the recurrent cancer is a recurrentperitoneal cancer. In some embodiments, the recurrent cancer is arecurrent fallopian tube cancer (including for example papillary serousadenocarcinomas, sarcomas, and transitional cell carcinomas).

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein theindividual has received a prior chemotherapy and has a treatment freeinterval for more about any of 3, 6, 9 months since the completion ofprior chemotherapy. In some embodiments, there is provided a method oftreating a recurrent cancer (such as a recurrent gynecological cancerfor example recurrent ovarian, peritoneal, or fallopian tube cancer) inan individual, comprising administering to the individual an effectiveamount of a composition comprising nanoparticles comprising a taxane(such as paclitaxel) and a carrier protein (such as albumin), whereinthe individual has received a prior chemotherapy and has a treatmentfree interval for more about any of 12, 18, 24, 36, or 48 months sincethe completion of prior chemotherapy. In some embodiments, the priorchemotherapy has a different mechanism of action than that of thetaxane-based therapy. In some embodiments, the individual has only beentreated with platinum-based agent(s) prior to the administration of thetaxane nanoparticle composition. In some embodiments, the individual hasonly been treated with one dosing regime prior to the administration ofthe taxane nanoparticle composition. In some embodiments, the individualhas not previously been treated with a taxane-based therapy.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein theindividual has received prior platinum-based chemotherapy and has atreatment free interval for more than about any of 3, 6, 9 months sincethe completion of the platinum-based chemotherapy. In some embodiments,there is provided a method of treating a recurrent cancer (such as arecurrent gynecological cancer for example recurrent ovarian,peritoneal, or fallopian tube cancer) in an individual, comprisingadministering to the individual an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), wherein the individual has receivedprior platinum-based chemotherapy and has a treatment free interval formore than about any of 12, 18, 24, 36, or 38 months since the completionof the platinum-based chemotherapy. In some embodiments, the methodfurther comprises administering to the individual an effective amount ofa platinum-based agent (such as carboplatin). In some embodiments, thecomposition comprising nanoparticles comprising a taxane and a carrierprotein is not administered in conjunction with a platinum agent, thatis, the composition comprising nanoparticles comprising a taxane and acarrier protein is either administered alone or administered inconjunction with a chemotherapeutic agent other than a platinum-basedagent.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein theindividual has received a prior chemotherapy and has a treatment freeinterval for more about any of 3, 6, 9 months prior to the initiation ofthe treatment method with the taxane nanoparticle composition. In someembodiments, there is provided a method of treating a recurrent cancer(such as a recurrent gynecological cancer for example recurrent ovarian,peritoneal, or fallopian tube cancer) in an individual, comprisingadministering to the individual an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), wherein the individual has received aprior chemotherapy and has a treatment free interval for more about anyof 12, 18, 24, 36, or 48 months prior to the initiation of the treatmentmethod with the taxane nanoparticle composition. In some embodiments,the prior chemotherapy has a different mechanism of action than that ofthe taxane-based therapy. In some embodiments, the individual has onlybeen treated with platinum-based agent(s) prior to the administration ofthe taxane nanoparticle composition. In some embodiments, the individualhas only been treated with one dosing regime prior to the administrationof the taxane nanoparticle composition. In some embodiments, theindividual has not previously been treated with a taxane-based therapy.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein theindividual has received prior platinum-based chemotherapy and has atreatment free interval for more than about any of 3, 6, 9 months priorto the initiation of the treatment method with the taxane nanoparticlecomposition. In some embodiments, there is provided a method of treatinga recurrent cancer (such as a recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, or fallopian tube cancer) in anindividual, comprising administering to the individual an effectiveamount of a composition comprising nanoparticles comprising a taxane(such as paclitaxel) and a carrier protein (such as albumin), whereinthe individual has received prior platinum-based chemotherapy and has atreatment free interval for more than about any of 12, 18, 24, 36, or 38months prior to the initiation of the treatment method with the taxanenanoparticle composition. In some embodiments, the method furthercomprises administering to the individual an effective amount of aplatinum-based agent. In some embodiments, the composition comprisingnanoparticles comprising a taxane and a carrier protein is notadministered in conjunction with a platinum agent, that is, thecomposition comprising nanoparticles comprising a taxane and a carrierprotein is either administered alone or administered in conjunction witha chemotherapeutic agent other than a platinum-based agent.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein theindividual does not show a symptom of hypersensitivity (such asneuropathy) prior to the initiation of the treatment method with thetaxane nanoparticle composition. In some embodiments, there is provideda method of treating a recurrent cancer (such as a recurrentgynecological cancer for example recurrent ovarian, peritoneal, orfallopian tube cancer) in an individual, comprising administering to theindividual an effective amount of a composition comprising nanoparticlescomprising a taxane (such as paclitaxel) and a carrier protein (such asalbumin), wherein the individual does not show a symptom ofhypersensitivity throughout the treatment period. In some embodiments,there is provided a method of treating a recurrent cancer (such as arecurrent gynecological cancer for example recurrent ovarian,peritoneal, or fallopian tube cancer) in an individual, comprisingadministering to the individual an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), wherein the individual does not showsymptoms of hypersensitivity upon completion of the treatment.

In some embodiments, the composition comprising nanoparticles comprisinga taxane and a carrier protein is administered alone. For example, insome embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein the amountof the composition administered to the individual alone is effective toresult in a complete response in the individual. In some embodiments,there is provided a method of treating a recurrent cancer (such as arecurrent gynecological cancer for example recurrent ovarian,peritoneal, or fallopian tube cancer) in an individual, comprisingadministering to the individual an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), wherein the amount of the compositionadministered to the individual alone is effective to result in a partialresponse in the individual.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein the amountof the composition administered to the individual alone is sufficient toproduce an overall response rate of more than about any of 40%, 50%,60%, or 64% among a population of individuals treated with thecomposition. In some embodiments, there is provided a method of treatinga recurrent cancer (such as a recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, or fallopian tube cancer) in anindividual, comprising administering to the individual an effectiveamount of a composition comprising nanoparticles comprising a taxane(such as paclitaxel) and a carrier protein (such as albumin), whereinthe amount of the composition administered to the individual alone issufficient to produce clinical benefit of more than about any of 50%,60%, 70%, or 77% among a population of individuals treated with thecomposition.

In some embodiments, the method comprises administering to theindividual an effective amount of a composition comprising nanoparticlescomprising paclitaxel and albumin. In some embodiments, the methodcomprises administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein average ormean diameter of the nanoparticles in the composition is less than about200 nm. In some embodiments, the method comprises administering to theindividual an effective amount of a composition comprising nanoparticlescomprising a taxane (such as paclitaxel) and a carrier protein (such asalbumin), wherein the nanoparticles comprise taxane coated with acoating comprising the carrier protein. In some embodiments, the methodcomprises administering to the individual an effective amount of aNab-paclitaxel (such as Abraxane®). For example, in some embodiments,there is provided a method of treating a platinum-sensitive recurrentovarian, peritoneal, or fallopian tube cancer in the individual,comprising administering to the individual an effective amount ofNab-paclitaxel or Abraxane®.

In some embodiments, there is provided a method of treating a recurrentovarian, peritoneal, or fallopian tube cancer (such as aplatinum-resistant ovarian, peritoneal, or fallopian tube cancer) in anindividual, comprising administering to the individual about 50 mg/m² toabout 300 mg/m² (including for example about 260 mg/m²) Nab-paclitaxelor Abraxane®. In some embodiments, the Nab-paclitaxel or Abraxane® isadministered every three weeks. In some embodiments, the Nab-paclitaxelor Abraxane® is administered intravenously (such as by i.v. infusionover a period of about 30 minutes or less). In some embodiments, theNab-paclitaxel or Abraxane® is administered intraperitoneally.

The methods of the present invention are useful for any one or more ofthe following (and thus in various embodiments can achieve and/orinclude any one or more of the following): 1) decreasing one or moresymptoms resulting from recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer); 2) increasing overall response rate of arecurrent cancer (such as recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, and fallopian tube cancer); 3) increasingpartial response rate of a recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer); 4) increasing complete response rate of arecurrent cancer (such as recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, and fallopian tube cancer); 5) delayingdisease progression of an individual with a recurrent cancer (such asrecurrent gynecological cancer for example recurrent ovarian,peritoneal, and fallopian tube cancer); 6) increasing the quality oflife in an individual with recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer); 7) prolonging overall survival of an individualhaving recurrent cancer (such as recurrent gynecological cancer forexample recurrent ovarian, peritoneal, and fallopian tube cancer); and8) prolonging progression-free survival of an individual havingrecurrent cancer (such as recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, and fallopian tube cancer).

Accordingly, in some embodiments, there is provided a method ofdecreasing one or more symptoms resulting from a recurrent cancer (suchas recurrent gynecological cancer for example recurrent ovarian,peritoneal, and fallopian tube cancer), comprising administering to theindividual an effective amount of a composition comprising nanoparticlescomprising a taxane (such as paclitaxel) and a carrier protein (such asalbumin). In some embodiments, there is provided a method of decreasingone more symptoms resulting from a recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer), comprising administering to the individual aneffective amount of Nab-paclitaxel or Abraxane®.

In some embodiments, there is provided a method of increasing responserate of recurrent cancer (such as recurrent gynecological cancer forexample recurrent ovarian, peritoneal, and fallopian tube cancer),comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin). In someembodiments, there is provided a method of increasing response rate ofrecurrent cancer (such as recurrent gynecological cancer for examplerecurrent ovarian, peritoneal, and fallopian tube cancer), comprisingadministering to the individual an effective amount of Nab-paclitaxel orAbraxane®.

In some embodiments, there is provided a method of delaying diseaseprogression of an individual with recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer), comprising administering to the individual aneffective amount of a composition comprising nanoparticles comprising ataxane (such as paclitaxel) and a carrier protein (such as albumin). Insome embodiments, there is provided a method of delaying diseaseprogression of an individual with recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer), comprising administering to the individual aneffective amount of Nab-paclitaxel or Abraxane®.

In some embodiments, there is provided a method of prolonging survivalof an individual having recurrent cancer (such as recurrentgynecological cancer for example recurrent ovarian, peritoneal, andfallopian tube cancer), comprising administering to the individual aneffective amount of a composition comprising nanoparticles comprising ataxane (such as paclitaxel) and a carrier protein (such as albumin). Insome embodiments, there is provided a method of prolonging survival ofan individual having recurrent cancer (such as recurrent gynecologicalcancer for example ovarian, peritoneal, and fallopian tube cancer),comprising administering to the individual an effective amount ofNab-paclitaxel or Abraxane®.

In some embodiments, there is provided a method of treating a recurrentovarian, peritoneal, or fallopian tube cancer in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane and a carrierprotein, wherein one or more symptoms resulting from the recurrentcancer is decreased. In some embodiments, there is provided a method oftreating a recurrent ovarian, peritoneal, or fallopian tube cancer in anindividual, comprising administering to the individual an effectiveamount of a composition comprising nanoparticles comprising a taxane anda carrier protein, wherein the individual has a partial response totreatment upon completion of less than about any of one, two, three,four, five, six, seven, or eight treatment cycles. In some embodiments,there is provided a method of treating a recurrent ovarian, peritoneal,or fallopian tube cancer in an individual, comprising administering tothe individual an effective amount of a composition comprisingnanoparticles comprising a taxane and a carrier protein, wherein theindividual has a complete response to treatment upon completion of lessthan about any of one, two, three, four, five, six, seven, or eighttreatment cycles. In some embodiments, the treatment cycle is fourweeks. In some embodiments, the treatment cycle is three weeks.

In some embodiments, there is provided a method of treating a recurrentovarian, peritoneal, or fallopian tube cancer in an individual,comprising administering to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane and a carrierprotein, wherein the individual is disease free for at least about anyof 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, or 24months upon completion of the treatment. In some embodiments, there isprovided a method of treating a recurrent ovarian, peritoneal, orfallopian tube cancer in an individual, comprising administering to theindividual an effective amount of a composition comprising nanoparticlescomprising a taxane and a carrier protein, wherein the individual doesnot show a symptom resulting from the recurrent cancer for at leastabout any of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22,or 24 months upon completion of the treatment. In some embodiments,there is provided a method of treating a recurrent ovarian, peritoneal,or fallopian tube cancer in an individual, comprising administering tothe individual an effective amount of a composition comprisingnanoparticles comprising a taxane and a carrier protein, wherein theindividual has a reduced CA-125 level (such as a level below about anyof 70%, 60%, 50%, 40%, 30%, 20%, 10% of the level prior to thetreatment) upon completion of the treatment. In some embodiments, theindividual has a reduced CA-125 level for at least about any of 0.5, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, or 24 months uponcompletion of the treatment.

In some embodiments, there is provided a method of treating a recurrentovarian, peritoneal, or fallopian tube cancer in an individual,comprising administering (for example intravenously orintraperitoneally) to the individual an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), wherein the amountof the taxane per administration is at least about 50 mg/m² (such as atleast about any of 70 mg/m², 100 m g/m², 150 mg/m², 200 mg/m², or 260mg/m²), and wherein one or more symptoms resulting from the recurrentcancer is decreased. In some embodiments, there is provided a method oftreating a recurrent ovarian, peritoneal, or fallopian tube cancer in anindividual, comprising administering (for example intravenously orintraperitoneally) to the individual an effective amount of Abraxane®,wherein the amount of paclitaxel per administration is at least about 50mg/m² (such as at least about any of 70 mg/m², 100 mg/m², 150 mg/m², 200mg/m², or 260 mg/m²), and wherein one or more symptoms resulting fromthe recurrent cancer is decreased. In some embodiments, the compositionis administered once every three weeks. In some embodiments, thecomposition is administered weekly. In some embodiments, the compositionis administered three out of four weeks. In some embodiments, theindividual does not show a symptom of hypersensitivity (such asneuropathy) prior to the initiation of the treatment. In someembodiments, the individual does not show a symptom of hypersensitivitythroughout the treatment period. In some embodiments, the individualdoes not show a symptom of hypersensitivity upon completion of thetreatment.

In some embodiments, the taxane nanoparticle composition is administeredin conjunction with another chemotherapeutic agent (such as aplatinum-based agent). For example, in some embodiments, the taxanenanoparticle composition and the other chemotherapeutic agent (such as aplatinum-based agent) are administered simultaneously. The term“simultaneous administration,” as used herein, means that the taxanenanoparticle composition and the other chemotherapeutic agent areadministered with a time separation of no more than about 15 minute(s),such as no more than about any of 10, 5, or 1 minutes. When the drugsare administered simultaneously, the taxane in the nanoparticles and theother chemotherapeutic agent may be contained in the same composition(e.g., a composition comprising both the nanoparticles and the otherchemotherapeutic agent) or in separate compositions (e.g., thenanoparticles are contained in one composition and the otherchemotherapeutic agent is contained in another composition). Forexample, the taxane and the other chemotherapeutic agent may be presentin a single composition containing at least two different nanoparticles,wherein some of the nanoparticles in the composition comprise the taxaneand a carrier protein, and some of the other nanoparticles in thecomposition comprise the other chemotherapeutic agent and a carrierprotein. In some embodiments, only the taxane is contained innanoparticles. In some embodiments, simultaneous administration of thedrug in the nanoparticle composition and the other chemotherapeuticagent can be combined with supplemental doses of the taxane and/or theother chemotherapeutic agent.

In some embodiments, the nanoparticle composition and the otherchemotherapeutic agent (such as the platinum-based agent) areadministered sequentially. The term “sequential administration” as usedherein means that the taxane in the nanoparticle composition and theother chemotherapeutic agent are administered with a time separation, ofmore than about 15 minutes, such as more than about any of 20, 30, 40,50, 60 or more minutes. Either the nanoparticle composition or the otherchemotherapeutic agent may be administered first. The nanoparticlecomposition and the other chemotherapeutic agent are contained inseparate compositions, which may be contained in the same or differentpackages.

In some embodiments, the administration of the nanoparticle compositionand the other chemotherapeutic agent are concurrent, i.e., theadministration period of the nanoparticle composition and that of theother chemotherapeutic agent overlap with each other. In someembodiments, the nanoparticle composition and the other chemotherapeuticagent are administered in the same treatment cycle(s).

The dosing frequency of the drug-containing nanoparticle composition andthe other chemotherapeutic agent may be adjusted over the course of thetreatment, based on the judgment of the administering physician. Whenadministered separately, the drug-containing nanoparticle compositionand the other chemotherapeutic agent can be administered at differentdosing frequency or intervals. For example, the drug-containingnanoparticle composition can be administered weekly, while achemotherapeutic agent can be administered more or less frequently. Insome embodiments, sustained continuous release formulation of thedrug-containing nanoparticle and/or chemotherapeutic agent may be used.Various formulations and devices for achieving sustained release areknown in the art.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), and b) an effectiveamount of a platinum-based agent. In some embodiments, there is provideda method of treating a recurrent cancer (such as a recurrentgynecological cancer, for example recurrent ovarian, peritoneal, orfallopian tube cancer) in an individual, comprising administering to theindividual a) an effective amount of a composition comprisingnanoparticles comprising paclitaxel and an albumin (such as Abraxane®),and b) an effective amount of a platinum-based agent. Suitableplatinum-based agents include, but are not limited to, carboplatin,cisplatin, and oxaliplatin. In some embodiments, the platinum-basedagent is carboplatin. In some embodiments, the taxane nanoparticlecomposition and the platinum-based agent are administeredsimultaneously. In some embodiments, the taxane nanoparticle compositionand the platinum-based agent are administered sequentially. In someembodiments, the taxane nanoparticle composition and the platinum-basedagent is administered concurrently.

In some embodiments, there is provided a method of treating a recurrentovarian cancer in an individual, comprising administering to theindividual: a) an effective amount of a composition comprisingnanoparticles comprising a taxane (such as paclitaxel) and a carrierprotein (such as albumin), and b) an effective amount of aplatinum-based agent. In some embodiments, there is provided a method oftreating a primary peritoneal cancer in an individual, comprisingadministering to the individual: a) an effective amount of a compositioncomprising nanoparticles comprising a taxane (such as paclitaxel) and acarrier protein (such as albumin), and b) an effective amount of aplatinum-based agent.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a taxane (such aspaclitaxel) and a carrier protein (such as albumin), and b) an effectiveamount of a platinum-based agent, wherein the taxane nanoparticlecomposition and the platinum-based agent are administered concurrently.In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a paclitaxel and analbumin (such as Abraxane®), and b) an effective amount of aplatinum-based agent, wherein the paclitaxel nanoparticle compositionand the platinum-based agent are administered concurrently.

In some embodiments, there is provided a method of treating a recurrentcancer (such as a recurrent gynecological cancer, for example recurrentovarian, peritoneal, or fallopian tube cancer) in an individual,comprising administering (for example intravenously orintraperitoneally) to the individual: a) an effective amount of acomposition comprising nanoparticles comprising a paclitaxel and analbumin (such as Abraxane®), wherein the amount of the paclitaxel in thecomposition is at least about 40 mg/m² (including for example about anyof 50 mg/m², 60 mg/m², 70 mg/m², 80 mg/m², 90 mg/m², 100 mg/m², 150mg/m², or 200 mg/m²); b) an effective amount of a platinum-based agent(such as the platinum-based agent at the amount of AUC3, AUC4, or AUC6),wherein the taxane nanoparticle composition and the platinum-based agentare administered concurrently. In some embodiments, the method comprisesadministering a composition comprising nanoparticles comprisingpaclitaxel and an albumin (such as Abraxane®) at about 100 mg/m², threeout of four weeks, and a platinum-based agent (such as carboplatin) AUC6every four weeks in the same treatment cycle. In some embodiments, themethod comprises administering a composition comprising nanoparticlescomprising paclitaxel and an albumin (such as Abraxane®) at about 100mg/m², three out of four weeks, and a platinum-based agent (such ascarboplatin) AUC5 every four weeks in the same treatment cycle. In someembodiments, the method comprises intravenously administering acomposition comprising nanoparticles comprising paclitaxel and analbumin (such as Abraxane®) at about 100 mg/m², three out of four weeks,and intravenously administering a platinum-based agent (such ascarboplatin) AUC5 every four weeks in the same treatment cycle. In someembodiments, the individual is treated with at least any of about one,two, three, four, five, six, seven, eight, or more such treatmentcycles.

In some embodiments, there is provided a method of treating recurrentovarian cancer, comprising intravenously administering a compositioncomprising nanoparticles comprising paclitaxel and an albumin (such asAbraxane®) at about 100 mg/m², three out of four weeks, andintravenously administering a platinum-based agent (such as carboplatin)AUC5 (or AUC6) every four weeks in the same treatment cycle. In someembodiments, there is provided a method of treating primary peritonealcancer, comprising intravenously administering a composition comprisingnanoparticles comprising paclitaxel and an albumin (such as Abraxane®)at about 100 mg/m², three out of four weeks, and intravenouslyadministering a platinum-based agent (such as carboplatin) AUC5 (orAUC6) every four weeks in the same treatment cycle. In some embodiments,the individual is treated with at least any of about one, two, three,four, five, six, seven, eight, or more such treatment cycles.

Individual Having Recurrent Cancer

The present invention provides a method of treating a recurrent cancer(such as recurrent gynecological cancer for example recurrent ovarian,peritoneal, and fallopian tube cancer) in an individual. A “recurrent”cancer is one which has regrown, either at the initial site or at adistant site, after a response to initial therapy. In some embodiments,the length of time between the completion of initial therapy and thedevelopment of recurrent disease is longer than about 3 month, includingfor example longer than about any of 4, 5, 6, 7, 8, 9, 10, or 11 months.In some embodiments, the length of time between the completion ofinitial therapy and the development of recurrent disease is longer thanabout 12 month, including for example, longer than about any of 14, 16,18, 20, 22, 24, 36, or 48 months.

In some embodiments, the recurrent cancer is a recurrent gynecologicalcancer. “Gynecologic cancer” used herein refers to a cancer originatingin the female reproductive organs. It includes cancers of the cervix,fallopian tubes, ovaries, uterus, vagina and vulva. In some embodiments,the recurrent cancer is a recurrent ovarian cancer. In some embodiments,the cancer is ovarian epithelial cancer. Exemplary ovarian epithelialcancer histological classifications include: serous cystomas (e.g.,serous benign cystadenomas, serous cystadenomas with proliferatingactivity of the epithelial cells and nuclear abnormalities but with noinfiltrative destructive growth, or serous cystadenocarcinomas),mucinous cystomas (e.g., mucinous benign cystadenomas, mucinouscystadenomas with proliferating activity of the epithelial cells andnuclear abnormalities but with no infiltrative destructive growth, ormucinous cystadenocarcinomas), endometrioid tumors (e.g., endometrioidbenign cysts, endometrioid tumors with proliferating activity of theepithelial cells and nuclear abnormalities but with no infiltrativedestructive growth, or endometrioid adenocarcinomas), clear cell(mesonephroid) tumors (e.g., begin clear cell tumors, clear cell tumorswith proliferating activity of the epithelial cells and nuclearabnormalities but with no infiltrative destructive growth, or clear cellcystadenocarcinomas), unclassified tumors that cannot be allotted to oneof the above groups, or other malignant tumors.

In some embodiments, the recurrent cancer is a recurrent ovarian germcell tumor. Exemplary histologic subtypes include dysgerminomas or othergerm cell tumors (e.g., endodermal sinus tumors such as hepatoid orintestinal tumors, embryonal carcinomas, olyembryomas, choriocarcinomas,teratomas, or mixed form tumors). Exemplary teratomas are immatureteratomas, mature teratomas, solid teratomas, and cystic teratomas(e.g., dermoid cysts such as mature cystic teratomas, and dermoid cystswith malignant transformation). Some teratomas are monodermal and highlyspecialized, such as struma ovarii, carcinoid, struma ovarii andcarcinoid, or others (e.g., malignant neuroectodermal and ependymomas).

In some embodiments, the recurrent cancer is a recurrent peritonealcancer. In some embodiments, the recurrent cancer is a recurrentfallopian tube cancer (including for example papillary serousadenocarcinomas, sarcomas, and transitional cell carcinomas). Otherrecurrent cancers such as recurrent malignant mixed mullerian tumor andserous endo can also be treated.

Recurrence of ovarian, peritoneal, or fallopian tube cancer can bedetermined, for example, based on bimanual pelvic examinations, serialmeasurements of CA-125 or other tumor markers, one or more imagingstudies reassessments, and second-look laparotomy. Imaging studies suchas CT, PET, or a CT/PET combination can also be used. In someembodiments, recurrence of ovarian, peritoneal, or fallopian tube cancercan be determined based on Response Evaluation Criteria in Solid Tumors(RECIST).

“Individual” used herein refers to human. In some embodiments, theindividual is a woman who is about 40 to about 85 years old, includingfor example about 60 to about 70 years old. In some embodiments, theindividual has an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0-2 (such as any of 0, 1, or 2) prior to the administration ofthe taxane nanoparticle composition. In some embodiments, the individualhas received a prior chemotherapy and has a treatment free interval formore than about any of 3, 6, or 9 months since the completion of priorchemotherapy. In some embodiments, the individual has received a priorchemotherapy and has a treatment free interval for more than about anyof 12, 18, 24, 36, or 48 months since the completion of priorchemotherapy. In some embodiments, the prior chemotherapy has adifferent mechanism of action than that of the taxane. In someembodiments, the individual has only been treated with platinum-basedagent(s) prior to the administration of the taxane nanoparticlecomposition. In some embodiments, the individual has only been treatedwith one dosing regime prior to the administration of the taxanenanoparticle composition. In some embodiments, the individual has notpreviously been treated with a taxane-based therapy.

In some embodiments, when the method is directed to treatment of arecurrent ovarian, peritoneal, or fallopian tube cancer, the individualis confirmed of having an ovarian, peritoneal, or fallopian tube cancerhistologically or cytologically. In some embodiments, the individual isdetermined to have an ovarian, peritoneal, or fallopian tube cancerbased on RECIST. In some embodiments, the individual has an elevatedblood level of Cancer Antigen 125 (CA-125, for example a CA-125 level ofmore than about 40, 50, 60, 70, 80, or 90 units/ml, or about 2×, 3×, 4×,or more of that of the upper limit of a normal CA-125 level). In someembodiments, the individual has an altered expression level of anothermarker that is indicative of a recurrent ovarian, peritoneal, andfallopian tube cancer.

The individual being treated may have one or more risk factorsassociated with a higher probability of developing ovarian, peritoneal,and fallopian tube cancer. These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. In some embodiments, the individual may be ahuman who is genetically or otherwise predisposed to developing ovarian,peritoneal, and fallopian tube cancer, particularly recurrent ovarian,peritoneal, and fallopian tube cancer.

Individuals at risk for ovarian, peritoneal, and fallopian tube cancerinclude, for example, those having relatives who have experienced thisdisease, and those whose risk is determined by analysis of genetic orbiochemical markers. For example, the individual may be a human who hasa gene, genetic mutation, or polymorphism associated with ovarian cancer(e.g., BRCA1 or BRCA2) or has one or more extra copies of a geneassociated with ovarian cancer (e.g., one or more extra copies of theHER2 gene). In some embodiments, the individual is HER2 positive. Insome embodiments, the individual is HER2 negative. In some embodiments,the ovarian cancer is associated with basal cell nevus (Gorlin)syndrome, multiple endocrine neoplasia type 1 (MEN1), or hereditarynonpolyposis colon cancer (HNPCC).

In some embodiments, the individual satisfies at least two of thecriteria described above. For example, in some embodiments, theindividual has a measurable disease by RECIST and an elevated bloodlevel of CA-125. In some embodiments, the individual is confirmed ofhaving an ovarian cancer histologically or cytologically and has onlybeen treated with platinum-based agent(s) prior to administration of thenanoparticle compositions described above. In some embodiments, theindividual satisfies at least any of two, three, four, five, or morecriteria described above. In some embodiments, the individual satisfiesall criteria described above.

In some embodiments, the recurrent cancer is platinum sensitive. Forexample, in some embodiments, the individual has received priorplatinum-based chemotherapy and has a treatment-free interval for morethan about any of 3, 6, or 9 months since the completion of theplatinum-based chemotherapy. In some embodiments, the individual hasreceived prior platinum-based chemotherapy and has a treatment-freeinterval for more than about any of 12, 18, 24, 36, or 48 months sincethe completion of the platinum-based chemotherapy. In some embodiments,the recurrent cancer is a platinum-sensitive ovarian cancer. In someembodiments, the recurrent cancer is a platinum-sensitive peritonealcancer. In some embodiments, the recurrent cancer is aplatinum-sensitive fallopian tube cancer.

In some embodiments, the recurrent cancer (such as a recurrent ovarian,peritoneal, or fallopian tube cancer) is platinum resistant. By“platinum-resistant” cancer is meant that the individual with cancer hasprogressed while receiving platinum-based chemotherapy (i.e. the patientis “platinum refractory”).

By “platinum-based chemotherapy” is intended to mean therapy with one ormore platinum-based chemotherapeutic agents, optionally in combinationwith one or more other chemotherapeutic agents. A “platinum-basedchemotherapeutic agent” comprises an organic compound which containsplatinum as an integral part of the molecule. These agents are believedto inhibit cell growth by forming reactive platinum complexes which formintrastrand and interstrand cross-linking of DNA molecules and inhibitDNA synthesis. Examples of platinum-based chemotherapeutic agentsinclude carboplatin, cisplatin, and oxaliplatinum. In some embodiments,the platinum-based chemotherapy comprises treatment with onlyplatinum-based agents. In some embodiments, the platinum-basedchemotherapy comprises treatment with carboplatin.

Dosing and Method of Administration

The amount of the inventive composition administered to an individual(such as a human) may vary with the particular composition, the methodof administration, and the particular type of recurrent cancer beingtreated. The amount should be sufficient to produce a desirablebeneficial effect. For example, in some embodiments, the amount of thecomposition is effective to result in an objective response (such as apartial response or a complete response). In some embodiments, theamount of the taxane nanoparticle composition is sufficient to result ina complete response in the individual. In some embodiments, the amountof the taxane nanoparticle composition is sufficient to result in apartial response in the individual. In some embodiments, the amount ofthe taxane nanoparticle composition administered (for example whenadministered alone) is sufficient to produce an overall response rate ofmore than about any of 40%, 50%, 60%, or 64% among a population ofindividuals treated with the taxane nanoparticle composition. Responsesof an individual to the treatment of the methods described herein can bedetermined, for example, based on RECIST or CA-125 level. For example,when CA-125 is used, a complete response can be defined as a return to anormal range value of at least 28 days from the pretreatment value. Aparticle response can be defined as a sustained over 50% reduction fromthe pretreatment value.

In some embodiments, the amount of the composition is sufficient toprolong progress-free survival of the individual (for example asmeasured by RECIST or CA-125 changes). In some embodiments, the amountof the composition is sufficient to prolong overall survival of theindividual. In some embodiments, the amount of the composition (forexample when administered along) is sufficient to produce clinicalbenefit of more than about any of 50%, 60%, 70%, or 77% among apopulation of individuals treated with the taxane nanoparticlecomposition.

In some embodiments, the amount of the taxane (e.g., paclitaxel) in thecomposition is below the level that induces a toxicological effect(i.e., an effect above a clinically acceptable level of toxicity) or isat a level where a potential side effect can be controlled or toleratedwhen the composition is administered to the individual. In someembodiments, the amount of the composition is close to a maximumtolerated dose (MTD) of the composition following the same dosingregime. In some embodiments, the amount of the composition is more thanabout any of 80%, 90%, 95%, or 98% of the MTD.

In some embodiments, the amount of a taxane (e.g., paclitaxel) in thecomposition is included in any of the following ranges: about 0.5 toabout 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 toabout 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 toabout 225 mg, about 225 to about 250 mg, about 250 to about 300 mg,about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about450 mg, or about 450 to about 500 mg. In some embodiments, the amount ofa taxane (e.g., paclitaxel) or derivative thereof in the effectiveamount of the composition (e.g., a unit dosage form) is in the range ofabout 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about50 mg to about 200 mg. In some embodiments, the concentration of thetaxane (e.g., paclitaxel) in the composition is dilute (about 0.1 mg/ml)or concentrated (about 100 mg/ml), including for example any of about0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5mg/ml. In some embodiments, the concentration of the taxane (e.g.,paclitaxel) is at least about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml.

Exemplary effective amounts of a taxane (e.g., paclitaxel) in thenanoparticle composition include, but are not limited to, about any of25 mg/m², 30 mg/m², 50 mg/m², 60 mg/m², 75 mg/m², 80 mg/m², 90 mg/m²,100 mg/m², 120 mg/m², 125 mg/m², 150 mg/m², 160 mg/m², 175 mg/m², 180mg/m², 200 mg/m², 210 mg/m², 220 mg/m², 250 mg/m², 260 mg/m², 300 mg/m²,350 mg/m², 400 mg/m², 500 mg/m², 540 mg/m², 750 mg/m², 1000 mg/m², or1080 mg/m² of a taxane (e.g., paclitaxel). In various embodiments, thecomposition includes less than about any of 350 mg/m², 300 mg/m², 250mg/m², 200 mg/m², 150 mg/m², 120 mg/m², 100 mg/m², 90 mg/m², 50 mg/m²,or 30 mg/m² of a taxane (e.g., paclitaxel). In some embodiments, theamount of the taxane (e.g., paclitaxel) per administration is less thanabout any of 25 mg/m², 22 mg/m², 20 mg/m², 18 mg/m², 15 mg/m², 14 mg/m²,13 mg/m², 12 mg/m², 11 mg/m², 10 mg/m², 9 mg/m², 8 mg/m², 7 mg/m², 6mg/m², 5 mg/m², 4 mg/m², 3 mg/m², 2 mg/m², or 1 mg/m². In someembodiments, the effective amount of a taxane (e.g., paclitaxel) in thecomposition is included in any of the following ranges: about 1 to about5 mg/m², about 5 to about 10 mg/m², about 10 to about 25 mg/m², about 25to about 50 mg/m², about 50 to about 75 mg/m², about 75 to about 100mg/m², about 100 to about 125 mg/m², about 125 to about 150 mg/m², about150 to about 175 mg/m², about 175 to about 200 mg/m², about 200 to about225 mg/m², about 225 to about 250 mg/m², about 250 to about 300 mg/m²,about 300 to about 350 mg/m², or about 350 to about 400 mg/m².Preferably, the effective amount of a taxane (e.g., paclitaxel) in thecomposition is about 5 to about 300 mg/m², such as about 100 to about150 mg/m², about 120 mg/m², about 130 mg/m², or about 140 mg/m².

In some embodiments of any of the above aspects, the effective amount ofa taxane (e.g., paclitaxel) in the composition includes at least aboutany of 1 mg/kg, 2.5 mg/kg, 3.5 mg/kg, 5 mg/kg, 6.5 mg/kg, 7.5 mg/kg, 10mg/kg, 15 mg/kg, or 20 mg/kg. In various embodiments, the effectiveamount of a taxane (e.g., paclitaxel) in the composition includes lessthan about any of 350 mg/kg, 300 mg/kg, 250 mg/kg, 200 mg/kg, 150 mg/kg,100 mg/kg, 50 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg,5 mg/kg, 3.5 mg/kg, 2.5 mg/kg, or 1 mg/kg of a taxane (e.g.,paclitaxel).

Exemplary dosing frequencies include, but are not limited to, weeklywithout break; weekly, three out of four weeks; once every three weeks;once every two weeks; weekly, two out of three weeks. In someembodiments, the composition is administered about once every 2 weeks,once every 3 weeks, once every 4 weeks, once every 6 weeks, or onceevery 8 weeks. In some embodiments, the composition is administered atleast about any of 1×, 2×, 3×, 4×, 5×, 6×, or 7× (i.e., daily) a week.In some embodiments, the intervals between each administration are lessthan about any of 6 months, 3 months, 1 month, 20 days, 15, days, 12days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2days, or 1 day. In some embodiments, the intervals between eachadministration are more than about any of 1 month, 2 months, 3 months, 4months, 5 months, 6 months, 8 months, or 12 months. In some embodiments,there is no break in the dosing schedule. In some embodiments, theinterval between each administration is no more than about a week.

The administration of the composition can be extended over an extendedperiod of time, such as from about a month up to about seven years. Insome embodiments, the composition is administered over a period of atleast about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36,48, 60, 72, or 84 months. In some embodiments, the taxane (e.g.,paclitaxel) or derivative thereof is administered over a period of atleast one month, wherein the interval between each administration is nomore than about a week, and wherein the dose of the taxane (e.g.,paclitaxel) at each administration is about 0.25 mg/m² to about 75mg/m², such as about 0.25 mg/m² to about 25 mg/m² or about 25 mg/m² toabout 50 mg/m².

In some embodiments, the dosage of a taxane (e.g., paclitaxel) in ananoparticle composition can be in the range of 5-400 mg/m² when givenon a 3 week schedule, or 5-250 mg/m² when given on a weekly schedule.For example, the amount of a taxane (e.g., paclitaxel) is about 60 toabout 300 mg/m² (e.g., about 260 mg/m²).

Other exemplary dosing schedules for the administration of thenanoparticle composition (e.g., paclitaxel/albumin nanoparticlecomposition) include, but are not limited to, 100 mg/m², weekly, withoutbreak; 75 mg/m² weekly, 3 out of four weeks; 100 mg/m², weekly, 3 out of4 weeks; 125 mg/m², weekly, 3 out of 4 weeks; 125 mg/m², weekly, 2 outof 3 weeks; 130 mg/m², weekly, without break; 175 mg/m², once every 2weeks; 260 mg/m², once every 2 weeks; 260 mg/m², once every 3 weeks;180-300 mg/m², every three weeks; 60-175 mg/m², weekly, without break;20-150 mg/m² twice a week; and 150-250 mg/m² twice a week. The dosingfrequency of the composition may be adjusted over the course of thetreatment based on the judgment of the administering physician.

In some embodiments, the individual is treated for at least about any ofone, two, three, four, five, six, seven, eight, nine, or ten treatmentcycles.

The compositions described herein allow infusion of the composition toan individual over an infusion time that is shorter than about 24 hours.For example, in some embodiments, the composition is administered overan infusion period of less than about any of 24 hours, 12 hours, 8hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10minutes. In some embodiments, the composition is administered over aninfusion period of about 30 minutes.

In some embodiments, the invention provides a method of treating cancerin an individual by parenterally administering to the individual (e.g.,a human) an effective amount of a composition comprising nanoparticlesthat comprise a taxane (e.g., paclitaxel) and a carrier protein (e.g.,albumin such as human serum albumin). The invention also provides amethod of treating cancer in an individual by intravenous,intra-arterial, intramuscular, subcutaneous, inhalation, oral,intraperitoneal, nasally, or intra-tracheal administering to theindividual (e.g., a human) an effective amount of a compositioncomprising nanoparticles that comprise a taxane (e.g., paclitaxel) and acarrier protein (e.g., albumin such as human serum albumin). In someembodiments, the route of administration is intraperitoneal. In someembodiments, the route of administration is intravenous, intra-arterial,intramuscular, or subcutaneous. In various embodiments, about 5 mg toabout 500 mg, such as about 30 mg to about 300 mg or about 50 to about500 mg, of the taxane (e.g., paclitaxel) or derivative thereof isadministered per dose. In some embodiments, the taxane (e.g.,paclitaxel) or derivative thereof is the only pharmaceutically activeagent for the treatment of cancer that is contained in the composition.In some embodiments, the method comprises intraperitoneallyadministering composition comprising nanoparticles that comprise ataxane (e.g., paclitaxel) and a carrier protein (e.g., albumin such ashuman serum albumin) at the dose of any of about 60 mg/m², 80 mg/m², 100mg/m², 125 mg/m², and 150 mg/m².

Any of the compositions described herein can be administered to anindividual (such as human) via various routes, including, for example,intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral,inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous,intraocular, intrathecal, transmucosal, and transdermal. In someembodiments, sustained continuous release formulation of the compositionmay be used. In one variation of the invention, nanoparticles (such asalbumin nanoparticles) of the inventive compounds can be administered byany acceptable route including, but not limited to, orally,intramuscularly, transdermally, intravenously, through an inhaler orother air borne delivery systems and the like.

In some embodiments, paclitaxel-containing nanoparticles composition maybe administered with a second therapeutic compound and/or a secondtherapy. The dosing frequency of the paclitaxel-containing nanoparticlescomposition and the second compound may be adjusted over the course ofthe treatment based on the judgment of the administering physician. Insome embodiments, the first and second therapies are administeredsimultaneously, sequentially, or concurrently. When administeredseparately, the taxane (e.g., paclitaxel)-containing nanoparticlescomposition and the second compound can be administered at differentdosing frequency or intervals. For example, the taxane (e.g.,paclitaxel)-containing nanoparticle composition can be administeredweekly, while a second compound can be administered more or lessfrequently. In some embodiments, sustained continuous releaseformulation of the taxane (e.g., paclitaxel)-containing nanoparticleand/or second compound may be used. Various formulations and devices forachieving sustained release are known in the art. A combination of theadministration configurations described herein can be used.

When the taxane nanoparticle compositions are administered inconjunction with another chemotherapeutic agent, the nanoparticlecomposition and the other chemotherapeutic agent can be administeredusing the same route of administration or different routes ofadministration. In some embodiments (for both simultaneous andsequential administrations), the taxane in the nanoparticle compositionand the other chemotherapeutic agent are administered at a predeterminedratio. For example, in some embodiments, the ratio by weight of thetaxane in the nanoparticle composition and the other chemotherapeuticagent is about 1 to 1. In some embodiments, the weight ratio may bebetween about 0.001 to about 1 and about 1000 to about 1, or betweenabout 0.01 to about 1 and 100 to about 1. In some embodiments, the ratioby weight of the taxane in the nanoparticle composition and the otherchemotherapeutic agent is less than about any of 100:1, 50:1, 30:1,10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, and 1:1 In someembodiments, the ratio by weight of the taxane in the nanoparticlecomposition and the other chemotherapeutic agent is more than about anyof 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 30:1, 50:1, 100:1. Otherratios are contemplated.

The doses required for the taxane and/or the other chemotherapeuticagent may (but not necessarily) be lower than what is normally requiredwhen each agent is administered alone. Thus, in some embodiments, asubtherapeutic amount of the drug in the nanoparticle composition and/orthe other chemotherapeutic agent are administered. “Subtherapeuticamount” or “subtherapeutic level” refer to an amount that is less thanthe therapeutic amount, that is, less than the amount normally used whenthe drug in the nanoparticle composition and/or the otherchemotherapeutic agent are administered alone. The reduction may bereflected in terms of the amount administered at a given administrationand/or the amount administered over a given period of time (reducedfrequency).

In some embodiments, enough chemotherapeutic agent is administered so asto allow reduction of the normal dose of the drug in the nanoparticlecomposition required to effect the same degree of treatment by at leastabout any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more. Insome embodiments, enough drug in the nanoparticle composition isadministered so as to allow reduction of the normal dose of the otherchemotherapeutic agent required to effect the same degree of treatmentby at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, ormore.

In some embodiments, the dose of both the taxane in the nanoparticlecomposition and the other chemotherapeutic agent are reduced as comparedto the corresponding normal dose of each when administered alone. Insome embodiments, both the taxane in the nanoparticle composition andthe other chemotherapeutic agent are administered at a subtherapeutic,i.e., reduced, level. In some embodiments, the dose of the nanoparticlecomposition and/or the other chemotherapeutic agent is substantiallyless than the established maximum toxic dose (MTD). For example, thedose of the nanoparticle composition and/or the other chemotherapeuticagent is less than about 50%, 40%, 30%, 20%, or 10% of the MTD.

Metronomic Therapy Regimes

The present invention also provides metronomic therapy regimes for anyof the methods of treatment and methods of administration describedherein. Exemplary metronomic therapy regimes and embodiments for the useof metronomic therapy regimes are discussed below and disclosed in U.S.Ser. No. 11/359,286, filed Feb. 21, 2006, published as U.S. Pub. No.2006/0263434 (such as those described in paragraphs [0138] to [0157]),which is hereby incorporated by reference in its entirety. In someembodiments, the nanoparticle composition is administered over a periodof at least one month, wherein the interval between each administrationis no more than about a week, and wherein the dose of the taxane (e.g.,paclitaxel) at each administration is about 0.25% to about 25% of itsmaximum tolerated dose following a traditional dosing regime. In someembodiments, the nanoparticle composition is administered over a periodof at least two months, wherein the interval between each administrationis no more than about a week, and wherein the dose of the taxane (e.g.,paclitaxel) at each administration is about 1% to about 20% of itsmaximum tolerated dose following a traditional dosing regime. In someembodiments, the dose of a taxane (e.g., paclitaxel) per administrationis less than about any of 25%, 24%, 23%, 22%, 20%, 18%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the maximumtolerated dose. In some embodiments, any nanoparticle composition isadministered at least about any of 1×, 2×, 3×, 4×, 5×, 6×, or 7× (i.e.,daily) a week. In some embodiments, the intervals between eachadministration are less than about any of 6 months, 3 months, 1 month,20 days, 15, days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, theintervals between each administration are more than about any of 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12months. In some embodiments, the composition is administered over aperiod of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18,24, 30, 36, 48, 60, 72, or 84 months.

Carrier Proteins

Provided herein are also compositions comprising nanoparticles thatcomprise a taxane and a carrier protein for use in methods of treatment,methods of administration, and dosage regimes described herein. In someembodiments, the carrier protein is albumin. In some embodiments, thecarrier protein is human serum albumin.

Examples of suitable carrier proteins include proteins normally found inblood or plasma, which include, but are not limited to, albumin,immunoglobulin including IgA, lipoproteins, apolipoprotein B, α-acidglycoprotein, β-2-macroglobulin, thyroglobulin, transferin, fibronectin,factor VII, factor VIII, factor IX, factor X, and the like. In someembodiments, the carrier protein is a non-blood protein, such as casein,α-lactalbumin, or β-lactoglobulin. The carrier proteins may either benatural in origin or synthetically prepared. In some embodiments, thepharmaceutical acceptable carrier comprises albumin, such as human serumalbumin (HSA). HSA is a highly soluble globular protein of M_(r) 65K andconsists of 585 amino acids. HSA is the most abundant protein in theplasma and accounts for 70-80% of the colloid osmotic pressure of humanplasma. The amino acid sequence of HSA contains a total of 17 disulphidebridges, one free thiol (Cys 34), and a single tryptophan (Trp 214).Other albumins are contemplated, such as bovine serum albumin. Use ofsuch non-human albumins could be appropriate, for example, in thecontext of use of these compositions in non-human mammals, such as theveterinary animals (including domestic pets and agricultural animals).

Human serum albumin (HSA) has multiple hydrophobic binding sites (atotal of eight for fatty acids, an endogenous ligand of HSA) and binds adiverse set of drugs, especially neutral and negatively chargedhydrophobic compounds (Goodman et al., The Pharmacological Basis ofTherapeutics, 9^(th) ed, McGraw-Hill New York (1996)). Two high affinitybinding sites have been proposed in subdomains IIA and IIIA of HSA,which are highly elongated hydrophobic pockets with charged lysine andarginine residues near the surface which function as attachment pointsfor polar ligand features (see, e.g., Fehske et al., Biochem. Pharmcol.,30, 687-92 (1981), Vorum, Dan. Med. Bull., 46, 379-99 (1999),Kragh-Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., Nat.Struct. Biol., 5, 827-35 (1998), Sugio et al., Protein. Eng., 12, 439-46(1999), He et al., Nature, 358, 209-15 (1992), and Carter et al., Adv.Protein. Chem., 45, 153-203 (1994)).

The carrier protein (e.g., albumin) in the composition generally servesas a carrier for the taxane (e.g., paclitaxel) or derivative thereof,i.e., the carrier protein in the composition makes the taxane (e.g.,paclitaxel) or derivative thereof more readily suspendable in an aqueousmedium or helps maintain the suspension as compared to compositions notcomprising a carrier protein. This can avoid the use of toxic solventsfor solubilizing of the taxane (e.g., paclitaxel), and thereby canreduce one or more side effects of administration of the taxane (e.g.,paclitaxel) into an individual (e.g., human). In some embodiments, thecomposition is substantially free (e.g. free) of organic solvents orsurfactants. A composition is “substantially free of organic solvent” or“substantially free of surfactant” if the amount of organic solvent orsurfactant in the composition is not sufficient to cause one or moreside effect(s) in an individual when the composition is administered tothe individual. In some embodiments, the nanoparticles in thecomposition have a solid core. In some embodiments, the nanoparticles inthe composition have a core that is not aqueous (i.e., other thanaqueous core). In some embodiments, the nanoparticles of the compositionlack a polymeric matrix. In some embodiments, the nanoparticles of thecomposition are filter sterilizable. In some embodiments, thenanoparticles in the composition comprise at least one cross-linkedcarrier protein. In some embodiments, the nanoparticles in thecomposition comprise at least ten-percent of carrier protein that iscross-linked.

The taxane (e.g., paclitaxel) is “stabilized” in an aqueous suspensionif it remains suspended in an aqueous medium (e.g., without visibleprecipitation or sedimentation) for an extended period of time, such asfor at least about any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The suspension is generally,but not necessarily, suitable for administration to an individual (e.g.,human). Stability of the suspension is generally (but not necessarily)evaluated at storage temperature, such as room temperature (e.g., 20-25°C.) or refrigerated conditions (e.g., 4° C.). For example, a suspensionis stable at a storage temperature if it exhibits no flocculation orparticle agglomeration visible to the naked eye or when viewed under theoptical microscope at 1000 times, at about fifteen minutes afterpreparation of the suspension. Stability can also be evaluated underaccelerated testing conditions, such as at a temperature that is higherthan about 40° C.

In some embodiments, the composition comprises nanoparticles comprising(in various embodiments consisting essentially of) a taxane (e.g.,paclitaxel) and a carrier protein. When the taxane (e.g., paclitaxel) isin a liquid form, the particles or nanoparticles are also referred to asdroplets or nanodroplets. In some embodiments, taxane is coated with thecarrier protein. Particles (such as nanoparticles) of poorly watersoluble pharmaceutical agents have been disclosed in, for example, U.S.Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in U.S. Pat. App.Pub. No. 2005/0004002A1.

The amount of carrier protein in the composition described herein willvary depending on the taxane (e.g., paclitaxel) or derivative thereof,and other components in the composition. In some embodiments, thecomposition comprises a carrier protein in an amount that is sufficientto stabilize the taxane (e.g., paclitaxel) in an aqueous suspension, forexample, in the form of a stable colloidal suspension (e.g., a stablesuspension of nanoparticles). In some embodiments, the carrier proteinis in an amount that reduces the sedimentation rate of the taxane (e.g.,paclitaxel) in an aqueous medium. The amount of the carrier protein alsodepends on the size and density of particles of the taxane (e.g.,paclitaxel).

In some embodiments of any of the aspects of the invention, the taxanesin the nanoparticles are coated with a carrier protein, such as albumin(e.g., human serum albumin). In some embodiments, the taxane ispaclitaxel. In various embodiments, the composition comprises more thanabout any of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the taxane orderivative thereof in nanoparticle form. In some embodiments, the taxaneor derivative thereof constitutes more than about any of 50%, 60%, 70%,80%, 90%, 95%, or 99% of the nanoparticles by weight. In someembodiments, the nanoparticles are substantially free of polymeric corematerials. In some embodiments, the taxane in the nanoparticles isamorphous. In some embodiments, the taxane used for making thenanoparticle compositions is in anhydrous form. In some embodiments, thecarrier protein (such as albumin) to a taxane weight ratio in the taxanenanoparticle composition is about any of 18:1 or less, 15:1 or less,14:1 or less, 13:1 or less, 12:1 or less, 11:1 or less, 10:1 or less,9:1 or less, 8:1 or less, 7.5:1 or less, 7:1 or less, 6:1 or less, 5:1or less, 4:1 or less, or 3:1 or less. In some embodiments, the albuminto taxane weight ratio is between about any of 18:1 to 1:18, 10:1 to1:10, 9:1 to 1:1, 8:1 to 1:1, 7.5:1 to 1.1, 7.1:1 to 1:1, 6:1 to 1:1,5:1 to 1:1, 4:1 to 1:1, or 3:1 to 1:1. In some embodiments, thecomposition comprises a stable aqueous suspension of particles (e.g.,nanoparticles) comprising a taxane and carrier protein (such as albumin,e.g., particles of paclitaxel coated with albumin).

In some embodiments, the composition comprises nanoparticles of anyshape (e.g., a spherical or non-spherical shape) with an average or meandiameter of no greater than about 1000 nanometers (nm), such as nogreater than about any of 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, or 50 nm. Insome embodiments, the average or mean diameter of the particles is nogreater than about 200 nm. In some embodiments, the composition issterile filterable. In some embodiments, the composition is sterilefiltered. In some embodiments, the average or mean diameter of theparticles is no greater than about 100 nm. In some embodiments, theaverage or mean diameter of the particles is between about 20 to about400 run. In some embodiments, the average or mean diameter of theparticles is between about 40 to about 200 nm. In some embodiments, theparticles are sterile-filterable. In some embodiments, the compositioncomprises nanoparticles with a diameter of about any of 1000 nm, 900 nm,800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm,80 nm, 70 nm, 60 nm, or 50 nm. In some embodiments, the compositioncomprises nanoparticles with a diameter of between about any of 50 nmand 150 nm, 50 nm and 75 nm, 50 nm and 100 nm, 75 nm and 100 nm, 100 nmand 125 nm, 125 nm and 150 nm, 100 nm and 150 nm, 150 nm and 175 nm, or175 nm and 200 nm. In some embodiments, the diameter of about any of 50%or more, 65% or more, 75% or more, 80% or more, 90% or more, 95% ormore, 98% or more, 99% or more, 99.5% or more, or 99.9% or more of thenanoparticles can fall within the range specified. Average or meandiameters of nanoparticles can be determined by methods known in theart, for example laser light scattering.

The nanoparticles described herein may be present in a dry formulation(e.g., lyophilized composition) or suspended in a biocompatible medium.Suitable biocompatible media include, but are not limited to, water,buffered aqueous media, saline, buffered saline, optionally bufferedsolutions of amino acids, optionally buffered solutions of proteins,optionally buffered solutions of sugars, optionally buffered solutionsof vitamins, optionally buffered solutions of synthetic polymers,lipid-containing emulsions, and the like.

In some embodiments, the nanoparticles do not comprise a blood-insolublegas or do not comprise gas-filled microbubbles.

In some embodiments, the carrier protein is present in an effectiveamount to reduce one or more side effects associated with administrationof taxane to a human compared to compositions without carrier protein.These side effects include, but are not limited to, myelosuppression,neurotoxicity, hypersensitivity, inflammation, venous irritation,phlebitis, pain, skin irritation, neutropenic fever, anaphylacticreaction, hematologic toxicity, and cerebral or neurologic toxicity, andcombinations thereof. In some embodiments, there is provided a method ofreducing hypersensitivity reactions associated with administration ofthe taxane (e.g., paclitaxel), including, for example, severe skinrashes, hives, flushing, dyspnea, tachycardia, pulmonary hypertension(e.g., lymphoma); chest pain; black, tarry stools; general feeling ofillness, shortness of breath; swollen glands; weight loss; yellow skinand eyes, abdominal pain; unexplained anxiousness; bloody or cloudyurine; bone pain; chills; confusion; convulsions (seizures); cough;decreased urge to urinate; fast, slow, or irregular heartbeat; fever;frequent urge to urinate; increased thirst; loss of appetite; lower backor side pain; mood changes; muscle pain or cramps; nausea or vomiting;numbness or tingling around lips, hands, or feet; painful or difficulturination; rash; sore throat; sores or white spots on lips or in mouth;swelling of hands, ankles, feet, or lower legs; swollen glands; troublebreathing; unusual bleeding or bruising; unusual tiredness or weakness;weakness or heaviness of legs, skin ulcer or sores, weight gain, acne;constipation; diarrhea; difficulty in moving; headache; loss of energyor weakness; muscle pain or stiffness; pain; shaking or trembling;trouble sleeping; nosebleed; and/or swelling of the face. These sideeffects, however, are merely exemplary and other side effects, orcombination of side effects, associated with the taxane (e.g.,paclitaxel) can be reduced. The side effects may be immediate or delayed(such as not occurring for a few days, weeks, months, or years aftertreatment begins).

Antimicrobial Agents in Compositions

In some embodiments, the compositions of the invention also includes anantimicrobial agent (e.g., an agent in addition to the taxane (e.g.,paclitaxel)) in an amount sufficient to significantly inhibit (e.g.,delay, reduce, slow, and/or prevent) microbial growth in the compositionfor use in the methods of treatment, methods of administration, anddosage regimes described herein. Exemplary microbial agents andvariations for the use of microbial agents are disclosed in U.S. Ser.No. 11/514,030, filed Aug. 30, 2006 (such as those described inparagraphs [0036] to [0058]). In some embodiments, the antimicrobialagent is a chelating agent, such as EDTA, edetate, citrate, pentetate,tromethamine, sorbate, ascorbate, derivatives thereof; or mixturesthereof. In some embodiments, the antimicrobial agent is a polydentatechelating agent. In some embodiments, the antimicrobial agent is anon-chelating agent, such as any of sulfites, benzoic acid, benzylalcohol, chlorobutanol, and paraben. In some embodiments, anantimicrobial other than the taxane discussed above is not contained orused in the methods of treatment, methods of administration, and dosageregimes described herein.

Sugar Containing Compositions

In some embodiments, the compositions of the invention include a sugarfor use in the methods of treatment described herein. In someembodiments, the compositions of the invention include both a sugar andan antimicrobial agent for use in the methods of treatment describedherein. Exemplary sugars and variations for the use of sugars aredisclosed in U.S. Ser. No. 11/514,030, filed Aug. 30, 2006 (such asthose described in paragraphs [0084] to [0090]). In some embodiments,the sugar serves as a reconstitution enhancer which causes a lyophilizedcomposition to dissolve or suspend in water and/or aqueous solution morequickly than the lyophilized composition would dissolve without thesugar. In some embodiments, the composition is a liquid (e.g., aqueous)composition obtained by reconstituting or resuspending a drycomposition. In some embodiments, the concentration of sugar in thecomposition is greater than about 50 mg/ml. In some embodiments, thesugar is in an amount that is effective to increase the stability of thetaxane (e.g., paclitaxel) or derivative thereof in the composition ascompared to a composition without the sugar. In some embodiments, thesugar is in an amount that is effective to improve filterability of thecomposition as compared to a composition without the sugar.

The sugar-containing compositions described herein may further compriseone or more antimicrobial agents, such as the antimicrobial agentsdescribed herein or in U.S. Ser. No. 11/514,030, filed Aug. 30, 2006. Inaddition to one or more sugars, other reconstitution enhancers (such asthose described in U.S. Pat. App. Publication No. 2005/0152979, which ishereby incorporated by reference in its entirety) can also be added tothe compositions. In some embodiments, a sugar is not contained or usedin the methods of treatment, methods of administration, and dosageregimes described herein.

Stabilizing Agents in Compositions

In some embodiments, the compositions of the invention also include astabilizing agent for use in the methods of treatment, methods ofadministration, and dosage regimes described herein. In someembodiments, the compositions of the invention include an antimicrobialagent and/or a sugar and/or a stabilizing agent for use in the methodsof treatment, methods of administration, and dosage regimes describedherein. Exemplary stabilizing agents and variations for the use ofstabilizing agents are disclosed in U.S. Ser. No. 11/513,756, filed Aug.30, 2006 (such as those described in paragraphs [0038] to [0083] and[0107] to [0114]). The present invention in another variation providesfor compositions and methods of preparation of a taxane (e.g.,paclitaxel) which retain the desirable therapeutic effects and remainphysically and/or chemically stable upon exposure to certain conditionssuch as prolonged storage, elevated temperature, or dilution forparenteral administration. The stabilizing agent includes, for example,chelating agents (e.g., citrate, malic acid, edetate, or pentetate),sodium pyrophosphate, and sodium gluconate. In some embodiments, theinvention provides pharmaceutical formulations of a taxane (e.g.,paclitaxel) comprising citrate, sodium pyrophosphate, EDTA, sodiumgluconate, citrate and sodium chloride, and/. In another variation, theinvention provides a composition of a taxane, wherein the taxane (e.g.,paclitaxel) used for preparing the formulation is in an anhydrous formprior to being incorporated into the composition.

In some embodiments, a stabilizing agent is not contained or used in themethods of treatment, methods of administration, and dosage regimesdescribed herein.

Pharmaceutical Compositions and Formulations

The compositions described herein may be used in the preparation of aformulation, such as a pharmaceutical formulation, by combining thenanoparticle composition(s) described with a pharmaceutical acceptablecarrier, excipients, stabilizing agents or other agent, which are knownin the art, for use in the methods of treatment, methods ofadministration, and dosage regimes described herein. To increasestability by increasing the negative zeta potential of nanoparticles,certain negatively charged components may be added. Such negativelycharged components include, but are not limited to bile salts, bileacids, glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholicacid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, litocholicacid, ursodeoxycholic acid, dehydrocholic acid, and others;phospholipids including lecithin (egg yolk) based phospholipids whichinclude the following phosphatidylcholines:palmitoyloleoylphosphatidylcholine,palmitoyllinoleoylphosphatidylcholine,stearoyllinoleoylphosphatidylcholine, stearoyloleoylphosphatidylcholine,stearoylarachidoylphosphatidylcholine, anddipalmitoylphosphatidylcholine. Other phospholipids includingL-α-dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine(DOPC), distearoylphosphatidylcholine (DSPC), hydrogenated soyphosphatidylcholine (HSPC), and other related compounds. Negativelycharged surfactants or emulsifiers are also suitable as additives, e.g.,sodium cholesteryl sulfate and the like.

In some embodiments, the composition is suitable for administration to ahuman. There are a wide variety of suitable formulations of theinventive composition (see, e.g., U.S. Pat. Nos. 5,916,596 and6,096,331, which are hereby incorporated by reference in theirentireties). The following formulations and methods are merely exemplaryand are in no way limiting. Formulations suitable for oraladministration can comprise (a) liquid solutions, such as an effectiveamount of the compound dissolved in diluents, such as water, saline, ororange juice, (b) capsules, sachets or tablets, each containing apredetermined amount of the active ingredient, as solids or granules,(c) suspensions in an appropriate liquid, (d) suitable emulsions, and(e) powders. Tablet forms can include one or more of lactose, mannitol,corn starch, potato starch, microcrystalline cellulose, acacia, gelatin,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, stearic acid, and other excipients, colorants, diluents,buffering agents, moistening agents, preservatives, flavoring agents,and pharmacologically compatible excipients. Lozenge forms can comprisethe active ingredient in a flavor, usually sucrose and acacia ortragacanth, as well as pastilles comprising the active ingredient in aninert base, such as gelatin and glycerin, or sucrose and acacia,emulsions, gels, and the like containing, in addition to the activeingredient, such excipients as are known in the art.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats, and solutes that render theformulation compatible with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizing agents, andpreservatives. The formulations can be presented in unit-dose ormulti-dose sealed containers, such as ampules and vials, and can bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid excipient methods of treatment, methodsof administration, and dosage regimes described herein (i.e., water) forinjection, immediately prior to use. Extemporaneous injection solutionsand suspensions can be prepared from sterile powders, granules, andtablets of the kind previously described. Injectable formulations arepreferred.

The invention also includes formulations of nanoparticle compositionscomprising the taxane (e.g., paclitaxel) or derivative thereof and acarrier suitable for administration by inhalation for use in the methodsof the invention. Formulations suitable for aerosol administrationcomprise the inventive composition include aqueous and non-aqueous,isotonic sterile solutions, which can contain anti-oxidants, buffers,bacteriostats, and solutes, as well as aqueous and non-aqueous sterilesuspensions that can include suspending agents, solubilizers, thickeningagents, stabilizing agents, and preservatives, alone or in combinationwith other suitable components, which can be made into aerosolformulations to be administered via inhalation. These aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like. They alsocan be formulated as pharmaceuticals for non-pressured preparations,such as in a nebulizer or an atomizer.

In some embodiments, the composition is formulated to have a pH in therange of about 4.5 to about 9.0, including for example pH ranges of anyof about 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 toabout 7.0. In some embodiments, the pH of the composition is formulatedto no less than about 6, including for example no less than about any of6.5, 7, or 8 (e.g., about 8). The composition can also be made to beisotonic with blood by the addition of a suitable tonicity modifier,such as glycerol.

The nanoparticles of this invention can be enclosed in a hard or softcapsule, can be compressed into tablets, or can be incorporated withbeverages or food or otherwise incorporated into the diet. Capsules canbe formulated by mixing the nanoparticles with an inert pharmaceuticaldiluent and inserting the mixture into a hard gelatin capsule of theappropriate size. If soft capsules are desired, a slurry of thenanoparticles with an acceptable vegetable oil, light petroleum or otherinert oil can be encapsulated by machine into a gelatin capsule.

Also provided are unit dosage forms comprising the compositions andformulations described herein. These unit dosage forms can be stored ina suitable packaging in single or multiple unit dosages and may also befurther sterilized and sealed. For example, the pharmaceuticalcomposition (e.g., a dosage or unit dosage form of a pharmaceuticalcomposition) may include (i) nanoparticles that comprise a taxane (e.g.,paclitaxel) and a carrier protein and (ii) a pharmaceutically acceptablecarrier. In some embodiments, the pharmaceutical composition alsoincludes one or more other compounds (or pharmaceutically acceptablesalts thereof) that are useful for treating cancer. In variousembodiments, the amount of a taxane (e.g., paclitaxel) in thecomposition is included in any of the following ranges: about 5 to about50 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 toabout 125 mg, about 125 to about 150 mg, about 150 to about 175 mg,about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350to about 400 mg, about 400 to about 450 mg, or about 450 to about 500mg. In some embodiments, the amount of a taxane (e.g., paclitaxel) orderivative thereof in the composition (e.g., a dosage or unit dosageform) is in the range of about 5 mg to about 500 mg, such as about 30 mgto about 300 mg or about 50 mg to about 200 mg, of the taxane (e.g.,paclitaxel) or derivative thereof. In some embodiments, the carrier issuitable for parental administration (e.g., intravenous administration).In some embodiments, the taxane (e.g., paclitaxel) or derivative thereofis the only pharmaceutically active agent for the treatment of cancerthat is contained in the composition.

In some embodiments, the invention features a dosage form (e.g., a unitdosage form) for the treatment of cancer comprising (i) nanoparticlesthat comprise a carrier protein and a taxane (e.g., paclitaxel), whereinthe amount of a taxane (e.g., paclitaxel) or derivative thereof in theunit dosage from is in the range of about 5 mg to about 500 mg, and (ii)a pharmaceutically acceptable carrier. In some embodiments, the amountof the taxane (e.g., paclitaxel) or derivative thereof in the unitdosage form includes about 30 mg to about 300 mg.

Also provided are articles of manufacture comprising the compositions,formulations, and unit dosages described herein in suitable packagingfor use in the methods of treatment, methods of administration, anddosage regimes described herein. Suitable packaging for compositionsdescribed herein are known in the art, and include, for example, vials(such as sealed vials), vessels (such as sealed vessels), ampules,bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags),and the like. These articles of manufacture may further be sterilizedand/or sealed.

Kits

The invention also provides kits comprising the compositions,formulations, unit dosages, and articles of manufacture described hereinfor use in the methods of treatment, methods of administration, anddosage regimes described herein. Kits of the invention include one ormore containers comprising a taxane (e.g., paclitaxel)-containingnanoparticle compositions (formulations or unit dosage forms and/orarticles of manufacture), and in some embodiments, further compriseinstructions for use in accordance with any of the methods of treatmentdescribed herein. In some embodiments, the kit comprises i) acomposition comprising nanoparticles comprising a taxane (e.g.,paclitaxel) and a carrier protein (such as albumin) and ii) instructionsfor administering the nanoparticles and the other chemotherapeuticagents simultaneously and/or sequentially, for treatment of cancer. Invarious embodiments, the amount of a taxane (e.g., paclitaxel) in thekit is included in any of the following ranges: about 5 mg to about 20mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 toabout 125 mg, about 125 to about 150 mg, about 150 to about 175 mg,about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350to about 400 mg, about 400 to about 450 mg, or about 450 to about 500mg. In some embodiments, the amount of a taxane (e.g., paclitaxel) inthe kit is in the range of about 5 mg to about 500 mg, such as about 30mg to about 300 mg or about 50 mg to about 200 mg. In some embodiments,the kit includes one or more other compounds (i.e., one or morecompounds other than a taxane) that are useful for cancer.

Instructions supplied in the kits of the invention are typically writteninstructions on a label or package insert (e.g., a paper sheet includedin the kit), but machine-readable instructions (e.g., instructionscarried on a magnetic or optical storage disk) are also acceptable. Theinstructions relating to the use of the nanoparticle compositionsgenerally include information as to dosage, dosing schedule, and routeof administration for the intended treatment. The kit may furthercomprise a description of selecting an individual suitable or treatment.

The present invention also provides kits comprising compositions (orunit dosages forms and/or articles of manufacture) described herein andmay further comprise instruction(s) on methods of using the composition,such as uses further described herein. In some embodiments, the kit ofthe invention comprises the packaging described above. In otherembodiments, the kit of the invention comprises the packaging describedabove and a second packaging comprising a buffer. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, syringes, andpackage inserts with instructions for performing any methods describedherein.

For combination therapies of the invention, the kit may containinstructions for administering the first and second therapiessimultaneously and/or sequentially for the effective treatment ofcancer. The first and second therapies can be present in separatecontainers or in a single container. It is understood that the kit maycomprise one distinct composition or two or more compositions whereinone composition comprises a first therapy and one composition comprisesa second therapy.

Kits may also be provided that contain sufficient dosages of the taxane(e.g., paclitaxel) as disclosed herein to provide effective treatmentfor an individual for an extended period, such as any of a week, 2weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months,6 months, 7 months, 8 months, 9 months or more. Kits may also includemultiple unit doses of the taxane (e.g., paclitaxel) compositions,pharmaceutical compositions, and formulations described herein andinstructions for use and packaged in quantities sufficient for storageand use in pharmacies, for example, hospital pharmacies and compoundingpharmacies. In some embodiments, the kit comprises a dry (e.g.,lyophilized) composition that can be reconstituted, resuspended, orrehydrated to form generally a stable aqueous suspension ofnanoparticles comprising a taxane (e.g., paclitaxel) and albumin (e.g.,a taxane (e.g., paclitaxel) coated with albumin).

The kits of the invention are in suitable packaging. Suitable packaginginclude, but is not limited to, vials, bottles, jars, flexible packaging(e.g., sealed Mylar or plastic bags), and the like. Kits may optionallyprovide additional components such as buffers and interpretativeinformation.

Methods of Making the Compositions

Methods of making compositions containing carrier proteins and poorlywater soluble pharmaceutical agents are known in the art. For example,nanoparticles containing poorly water soluble pharmaceutical agents andcarrier proteins (e.g., albumin) can be prepared under conditions ofhigh shear forces (e.g., sonication, high pressure homogenization, orthe like). These methods are disclosed in, for example, U.S. Pat. Nos.5,916,596; 6,506,405; and 6,537,579 and also in U.S. Pat. Pub. No.2005/0004002A1, which are each hereby incorporated by reference in theirentireties.

Briefly, the taxane (e.g., paclitaxel) is dissolved in an organicsolvent. Suitable organic solvents include, for example, ketones,esters, ethers, chlorinated solvents, and other solvents known in theart. For example, the organic solvent can be methylene chloride,chloroform/ethanol, or chloroform/t-butanol (for example with a ratio ofabout any of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1,5:1, 6:1, 7:1, 8:1, or 9:1 or with a ratio of about any of 3:7, 5:7,4:6, 5:5, 6:5, 8:5, 9:5, 9.5:5, 5:3, 7:3, 6:4, or 9.5:0.5). The solutionis added to a carrier protein (e.g., human serum albumin). The mixtureis subjected to high pressure homogenization (e.g., using an Avestin,APV Gaulin, Microfluidizer™ such as a Microfluidizer™ Processor M-110EHfrom Microfluidics, Stansted, or Ultra Turrax homogenizer). The emulsionmay be cycled through the high pressure homogenizer for between about 2to about 100 cycles, such as about 5 to about 50 cycles or about 8 toabout 20 cycles (e.g., about any of 8, 10, 12, 14, 16, 18 or 20 cycles).The organic solvent can then be removed by evaporation utilizingsuitable equipment known for this purpose, including, but not limitedto, rotary evaporators, falling film evaporators, wiped filmevaporators, spray driers, and the like that can be operated in batchmode or in continuous operation. The solvent may be removed at reducedpressure (such as at about any of 25 mm Hg, 30 mm Hg, 40 mm Hg, 50 mmHg, 100 mm Hg, 200 mm Hg, or 300 mm Hg). The amount of time used toremove the solvent under reduced pressure may be adjusted based on thevolume of the formulation. For example, for a formulation produced on a300 mL scale, the solvent can be removed at about 1 to about 300 mm Hg(e.g., about any of 5-100 mm Hg, 10-50 mm Hg, 20-40 mm Hg, or 25 mm Hg)for about 5 to about 60 minutes (e.g., about any of 7, 8, 9, 10, 11, 12,13, 14, 15 16, 18, 20, 25, or 30 minutes).

If desired, human albumin solution may be added to the dispersion toadjust the human serum albumin to the taxane (e.g., paclitaxel) ratio orto adjust the concentration of the taxane (e.g., paclitaxel) in thedispersion. For example, human serum albumin solution (e.g., 25% w/v)can be added to adjust the human serum albumin to a taxane (e.g.,paclitaxel) ratio to about any of 18:1, 15, :1 14:1, 13:1, 12:1, 11:1,10:1, 9:1, 8:1, 7.5:1, 7:1, 6:1, 5:1, 4:1, or 3:1. For example, humanserum albumin solution (e.g., 25% w/v) or another solution is added toadjust the concentration of a taxane (e.g., paclitaxel) in thedispersion to about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml,15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml. Thedispersion may be serially filtered through multiple filters, such as acombination of 1.2 μm and 0.8/0.2 μm filters; the combination of 1.2 μm,0.8 μm, 0.45 μm, and 0.22 μm filters; or the combination of any otherfilters known in the art. The dispersion obtained can be furtherlyophilized. The nanoparticle compositions may be made using a batchprocess or a continuous process (e.g., the production of a compositionon a large scale).

If desired, a second therapy (e.g., one or more compounds useful fortreating cancer), an antimicrobial agent, sugar, and/or stabilizingagent can also be included in the composition. This additional agent caneither be admixed with the taxane (e.g., paclitaxel) and/or the carrierprotein during preparation of the taxane (e.g., paclitaxel)/carrierprotein composition, or added after the taxane (e.g.,paclitaxel)/carrier protein composition is prepared. In someembodiments, the agent is admixed with the taxane (e.g.,paclitaxel)/carrier protein composition prior to lyophilization. In someembodiments, the agent is added to the lyophilized pharmaceuticalagent/carrier protein composition. In some embodiments when the additionof the agent changes the pH of the composition, the pH in thecomposition are generally (but not necessarily) adjusted to a desiredpH. Exemplary pH values of the compositions include, for example, in therange of about 5 to about 8.5. In some embodiments, the pH of thecomposition is adjusted to no less than about 6, including for exampleno less than any of about 6.5, 7, or 8 (e.g., about 8).

Unless defined otherwise, the meanings of all technical and scientificterms used herein are those commonly understood by one of skill in theart to which this invention belongs. One of skill in the art will alsoappreciate that any methods and materials similar or equivalent to thosedescribed herein can also be used to practice or test the invention.

The following Examples are provided to illustrate, but not limit, theinvention.

EXAMPLES

The examples, which are intended to be purely exemplary of the inventionand should therefore not be considered to limit the invention in anyway, also describe and detail aspects and variations of the inventiondiscussed above. Efforts have been made to ensure accuracy with respectto numbers used (for example, amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1 Exemplary Method for the Formation of NanoparticleCompositions with Paclitaxel and Albumin

This example provides formulations of paclitaxel/albumin. Thecompositions were prepared essentially as described in U.S. Pat. Nos.5,439,686 and 5,916,596. Briefly, paclitaxel was dissolved in an organicsolvent (such as methylene chloride or a chloroform/ethanol mixture),and the solution was added to a human serum albumin solution. Themixture was homogenized for 5 minutes at low RPM to form a crudeemulsion, and then transferred into a high pressure homogenizer. Theemulsification was performed at 9000-40,000 psi while recycling theemulsion for at least 5 cycles. The resulting system was transferredinto a rotary evaporator, and the organic solvent was rapidly removed at40° C., at reduced pressure (30 mm Hg) for 20-30 minutes. The dispersionwas then further lyophilized for 48 hours. The resulting cake wasreconstituted to the original dispersion by addition of sterile water orsaline, which may optionally contain additional antimicrobial agent(s).

Example 2 Evaluation of Efficacy of Nanoparticle Albumin BoundPaclitaxel (Nab-Paclitaxel) in Treating Platinum-Sensitive Patients withRecurrent Ovarian, Peritoneal, or Fallopian Tube Cancer

The primary objective of this study was to determine the objectiveresponse rate in platinum-sensitive patients with recurrent ovarian,peritoneal, or fallopian tube cancer. The study also evaluated theprogression free survival, overall survival, quality of life duringtreatment, and the safety and toxicity of the treatment in this patientpopulation.

Patient Population Evaluated

Patients were eligible for inclusion for inclusion in this study if shemet all of the following criteria: had histologically or cytologicallyconfirmed epithelial cancer of the ovary, fallopian tube or peritoneum(any stage, grade 2-3 if stage 1), had measurable disease by RECIST orelevated CA-125 (>70) in the absence of measurable disease, had receivedprior platinum-based chemotherapy, was considered platinum sensitive(i.e., having a treatment-free interval >6 months since completion ofplatinum base chemotherapy), had an ECOG Performance Status (PS) 0-2,had a present, existing peripheral neuropathy which was less than orequal to Grade 1, and had signed an Institutional Review Board approvedinformed consent. Patients were excluded from this study if she met anyof the following criteria: had previously untreated stage 1, Grade 1disease, was chemotherapy-naïve, had received more than one priorregimen or prior regimen that was not platinum-based, had non-epithelialdisease, had nonmeasurable disease with CA-125 less than or equal to 70,had received a taxane within 6 months of registration or any priortreatment with Nab-paclitaxel.

Treatment Schedule

Premedication was administered at the discretion of the treatingphysician. Patients received 260 mg/m² of Nab-paclitaxel (Abraxane®)administered IV during a 30-minute period on Day 1 of each 21-day cycle.Successive cycles were initiated every 3 weeks and were continued untilthere was evidence of disease progression, unacceptable toxicity, oruntil 6 cycles. In patients whose only disease measure was an elevatedCA-125, up to 3 cycles of treatment were to be administered at thediscretion of the treating physician before response was assessed.Patients who achieved a CR could have received an additional 2 cycles atthe discretion of the treating physician therefore, CR patients wereeligible to receive a maximum of 8 cycles.

Assessments

Baseline: Complete medical history and physical exam, assessment of ECOGperformance status and peripheral neuropathy, CBC, CMP, CA-125,pregnancy test (if appropriate), clinical and radiological assessment ofthe sites of disease, urinalysis, ECG, and completion FACT-O quality oflife questionnaire was determined.

During treatment (prior to the start of each cycle): brief medicalhistory and physical exam, assessment of ECOG performance status andperipheral neuropathy, CBC, CMP, CA-125, pregnancy test (ifappropriate), clinical and radiological assessment of tumor response,assessment of other sites of disease, toxicity assessments, andcompletion FACT-O quality of life questionnaire. These same assessmentswere made at the time that patients went off study treatment and every 3months for a total of 18 months after the last dose. Responses wereassessed by RECIST criteria, CA-125 criteria, or both. See Therasse P.et al., J. NCI 95:205-16 (2000). Response assessment using RECISTfollowed the commonly applied definitions.

Using CA-125, a complete response was defined as a return to a normalrange value for at least 28 days from the pretreatment value. See Rustinet al. Clin. Cancer Res. 10(11):3919-26 (2004). A partial response wasdefined as a sustained over 50% reduction from the pretreatment value.Stable disease was defined as a sustained greater than 50% increase inCA-125 over 28 days in the absence of any new clinically measurabledisease, after an adequate trial of therapy. Progressive disease wasdefined as a sustained over 50% increase in CA-125 or development of newclinically measurable disease after an adequate trial of therapy. Anincrease was measured from the nadir (the lowest CA-125 value sinceenrollment).

Patients who discontinued due to adverse events, PD, noncompliance, etc.were followed only for survival, additional therapy, site and date ofrelapse or progression. Adverse event data were collected for 30 daysfollowing last dose.

Patient Characteristics

The majority of enrolled patients had recurrence of disease great than12 months since prior platinum based chemotherapy.

TABLE 1 Patient characteristics. Number of Subjects Enrolled 47 Age(Years) Median 65.4   Range 42-84 Number and Percentage (%) of SubjectsRace White 41 (87.2) Black 1 (2.1) Hispanic 3 (6.4) Asian 1 (2.1) Indian1 (2.1) ECOG Performance Status* 0 38 (80.8) 1  9 (19.2) Prior Therapy**Prior Chemotherapy greater than or equal to 43 (91.5) 2 months PriorChemotherapy less than or equal to 12 4 (8.5) months Surgery 44 (93.6)Site of Primary Disease Epithelial ovarian 37 (78.7) Fallopian tube 1(2.1) Peritoneum  9 (19.2) Histological Grade GX (can not be assessed) 1(2.1) G1 (well differentiated) 4 (8.5) G2 (moderately differentiated)  9(19.2) G3 (poorly differentiated) 23 (48.9) Missing/Unknown 10 (21.3)*Assessed prior to first treatment **Subjects may not have more than oneprior chemotherapy regimen.

Status

TABLE 2 Patient Status. Total Number of Subjects 47 Number andPercentage (%) of Subjects Status Alive 44 (93.6) Dead 3 (6.4) Cause ofDeath Progressive disease 3   Reason for Discontinuation NormalCompletion 30 (63.8) Toxicity 1 (2.1) Patient Request/Withdrew Consent 2(4.2) Investigator decision 3 (6.4) Recurrence 10 (21.3) Other (Coronaryartery bypass surgery) 1 (2.1) Total Cycles Received Median 6.0 Range1-8

Response to Treatment

Overall response rates were calculated using either RECIST or CA-125 orboth, the ORR (CP+PR) was 63.2%. Three patients were not evaluable, twowere found to be ineligible after start of treatment, and one patientwas never treated. Overall survival and progression free survival wereplotted in terms of months (x-axis) to proportion of survival orproportion not progressed (y-axis), respectively. See FIGS. 1 a and 1 b.

TABLE 3 Patient Response Total Number of Eligible/Treated Subjects 44Best Response N (%) 95% Cl Complete Response 14 (31.8) (18.1, 45.6)Partial Response 14 (31.8) (18.1, 45.6) Stable disease 14 (31.8) (18.1,45.6) SD greater than or equal to 6 6 months SD less than 6 moths 8Progressive disease   2 (4.5%)   (0, 10.7) Clinical Benefit 34 (77.3)Non-evaluable 3 Time to Response (months) Median 1.8 Range 0.6-3.4 Duration of Response (months) Median 6.5 Range 2.7-13.2 95% Cl 6.6, NA

TABLE 4 Best Response. By RECIST Best Response By RECIST By CA-125 andCA-125 Complete Response 1 6 7 Partial Response 4 3 7 Stable disease 5 27 SD greater than or 3 0 3 equal to 6 months SD less than 6 moths 2 2 4Progressive disease 1 0 1 Clinical Benefit 8 9 17

Treatment-Related Toxicity >Grade 3

There were 56 patients treated. Grade 3 neuropathy occurred in 8.7% ofpatients.

TABLE 5 Treatment-related Grade 3-4 Toxicity in greater than or equal to2% of patients Grade Grade Adverse Event 3 4 Total Total % HematologicLeukopenia 6 0 6 13.0% Neutropenia 6 5 11 23.9% Nonhematologic Abdominalpain 1 0 1 2.2% Diarrhea 1 0 1 2.2% Fatigue 1 0 1 2.2% Neuropathy 4 0 48.7% Pneumonia 1 0 1 2.2% Upper 1 0 1 2.2% respiratory tract infectionGeneralized 1 0 1 2.2% weakness

TABLE 6 Incidences of Alopecia Alopecia Grade 1  5 (10.8%) Grade 2 35(76.1%)

Estimated Quality of Life

The Quality of Life (FACT-O) questionnaire was completed at baseline andbefore each cycle. Overall quality of life measured decreased frombaseline at the initiation of therapy. As measured by the questionnaire,the major contributors to the initial decline in quality of life werethe functional, social, and physical well being assessments. All measureimproved at the completion of therapy and returned to based line.

Conclusion

Nab-paclitaxel was very active as a single agent in patients withplatinum sensitive recurrent ovarian, peritoneal, or fallopian tubecancer. The ORR was 64% and the clinical benefit rate was 77%.Toxicities were tolerable and manageable.

Example 3 Evaluation of Efficacy of Nab-Paclitaxel Plus Carboplatin inTreating Patients with Recurrent Platinum-Sensitive Ovarian or PrimaryPeritoneal Cancer

This open-label, non-randomized study was designed to determine theefficacy and safety of nab-paclitaxel (a 130-nm albumin-bound particleform of paclitaxel) plus carboplatin in patients with metastatic ovarianor primary peritoneal carcinoma following platinum-based chemotherapy.

Methods

Eligible patients had to have either measurable disease (based on RECISTcriteria) or pretreatment CA-125 levels >2 times the upper limit ofnormal in the absence of measurable disease. Patients also had to havegood performance status, adequate hepatic/renal function, peripheralneuropathy <grade 1, and life expectancy >6 months. Patients may havereceived prior chemotherapy for ovarian cancer, includingtaxane-containing regimens, provided the treatment was completed atleast 6 months before enrollment. Nab-Paclitaxel 100 mg/m² wasadministered IV over 30 minutes on days 1, 8, and 15 every 28 days.Carboplatin AUC 6 was administered IV over 1-2 hours on day 1 every 28days. Treatment continued for 6 cycles (or longer in the absence ofunacceptable toxicity). Planned sample size was 43 patients (39evaluable). Efficacy was determined by changes in tumor size forpatients with measurable disease or changes in CA-125 levels for thosewith non-measurable disease.

Results

To date, 10 patients have been enrolled, 2 of whom completed 2 treatmentcycles; both patients had a 50% reduction in their disease (partialresponse). One patient had grade 4 neutropenia; grade 3 hematologicevents were neutropenia (2 patients), thrombocytopenia (3), and anemia(1). Severe headache and severe nausea were reported for 2 patientseach; all 4 events required medication.

Conclusions

Preliminary results indicated that nab-paclitaxel 100 mg/m2 pluscarboplatin AUC 6 will have antitumor activity in patients withrecurrent platinum-sensitive ovarian or primary peritoneal cancer andthat treatment appears to be well tolerated.

Example 3B Abraxane® Plus Carboplatin in Patients with RecurrentPlatinum-Sensitive Ovarian or Primary Peritoneal Cancer: Evaluation ofthe Response and Survival and Progression-Free Survival

The aim of this study was to evaluate the effectiveness of Abraxane®plus carboplatin in the treatment of patients with recurrentplatinum-sensitive ovarian or primary peritoneal cancer.

Methods

Patients with recurrent platinum-sensitive ovarian or primary peritonealcarcinoma with measurable or biological evidence of disease had receivedAbraxane® 100 mg/m² on days 1, 8, and 15 and carboplatin AUC 5 on day 1,every 28 days, intravenously for six cycles. In this study of patientswith advanced ovarian cancer, an interim data analysis was conducted ofthe first 29 of 43 patients who had completed six cycles of treatment.Patients were evaluated with respect to the safety, tolerability, andantitumor effect of intravenous Abraxane® plus carboplatin. Efficacy wasmeasured as changes from baseline in tumor size measured by CT usingRECIST Criteria, survival, progression-free survival, andrecurrence-free survival during treatment and post study. Safety andtolerability were monitored through adverse events and clinicallaboratory values, as well as physical examinations during study drugdosing.

Results

Twenty-six of 29 patients completed six cycles of chemotherapy. Completeresponse was attained by 20 of 29 (68.9%) patients. Partial responsebased on CT evaluation was achieved by four of 29 (13.8%) patients. Inone of 29 (3.4%) patients, tumor size increased after the second cycleand then decreased. Two of 29 (6.8%) patients progressed anddiscontinued treatment: one (1/29, 3.4%) discontinued treatmentsecondary to carboplatin toxicity and the other (1/29, 3.4%) patientdiscontinued treatment secondary to severe thrombocytopenia. Abraxane®plus carboplatin can be used to treat recurrent platinum-sensitiveovarian or primary peritoneal cancer effectively.

Example 4 Comparison of Pharmacokinetics of Intravenous andIntraperitoneal

The purpose of this study was to compare the pharmacokinetics ofintravenous and intraperitoneal administration of Nab-paclitaxel. Forintravenous administration, 20 rats were dosed with Abraxane® at 50mg/kg. Dose volume of 10 ml/kg was delivered intravenously via the tailvein. Blood was drawn at the following intervals for LC/MS/MS analysisof paclitaxel: 0.0, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72 hr. Forintraperitoneal administration, 3 rats were dosed with Abraxane® at 50mg/kg. Dose volume of 10 ml/kg was delivered intraperitoneally. Bloodwas drawn at the following intervals for LC/MS/MS analysis ofpaclitaxel: 0.0, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72 hr.

Results

The plasma level of paclitaxel was measured by LC/MS/MS analysis (FIG. 2and FIG. 3). As indicated in Table 7, intraperitoneal delivery leaded toa slow absorption of paclitaxel into the circulation with t_(max)occurring at ˜3 hrs. The terminal half-lives of paclitaxel whenadministered intraperitoneally or intravenously were about the same.Systemic exposure after IP administration was ˜50% of IV (over 72 hrs),indicating substantial local intraperitoneal exposure of drug,especially in the early phase (0-4 hrs) after administration. There maybe sustained exposure beyond 72 hrs; however, this study was terminatedat 72 hrs.

TABLE 7 Pharmacokinetics Parameters of Intravenous and IntraperitonealC_(max) AUC last AUC inf % AUC F HL (h) T_(max) (hr) (ng/ml) (hr*ng/ml)(hr*ng/ml) Extrapolate (%) IP (N = 3) 6.31 ± 0.20 3.33 ± 1.16 3207 ± 71726233 ± 3848 26770 ± 3904 2.0 ± 1.2 53 IV (N = 20) 7.96 ± 4.05 0.083 ±0.000 25060 ± 3573 50038 ± 6134 50146 ± 6137 0.2 ± 0.1

Example 5 Intraperitoneal Administration of Abraxane® in RecurrentMullerian Cancer

Intraperitoneal therapy for recurrent diseases is an area that requiresfurther study. The purpose of this experiment is to determine thesafety, efficacy, and maximum tolerable dose of Nab-paclitaxel whenadministered intraperitoneally.

Methods

A Phase I dose-escalation trial is conducted with 6 patients per cohortto provide sufficient pharmacokinetic data points. Every 4 weeks dosagesare escalated so that the cumulative toxicity of weekly treatment may beevaluated. When the MTD is reached, an additional 10 patients aretreated to obtain further information about the tolerability at thisdose continuously (or ¾ weeks) as well as preliminary informationregarding efficacy.

Intraperitoneal dosing of Abraxane® begins at 60 mg/m². Doses isescalated as follows: Dose level 1: 60 mg/m², Dose level 2: 80 mg/m²,Dose level 3: 100 mg/m², Dose level 4: 125 mg/m², and Dose level 5: 150mg/m². Ten patients are added at the DLT, and the study is expected toaccrue approximately 30-40 patients.

Patient Population

Patients are included in the study if they meet the following criteria:having recurrent Mullerian cancer (ovarian, peritoneal, fallopian tube,malignant mixed mullerian tumor, serous endo), having disease <1 cm byCT/MRI or SLO, displaying adequate heme/hepatic/renal function, and PS0-1. Patients are excluded based on meeting the following criteria:having a bowel obstruction (or impending), existing intra-abdominalinfection, having significant loculations/adhesions or othercontraindications to IP port placement, existing neuropathy >grade 1,having extraperitoneal disease, or displaying an inability to tolerateIV paclitaxel and docetaxel, suggestive of taxane allergy.

1. A method of treating a recurrent ovarian, peritoneal, or fallopiantube cancer in an individual, comprising administering to the individualan effective amount of a composition comprising nanoparticles comprisinga taxane and a carrier protein.
 2. The method of claim 1, wherein therecurrent ovarian, peritoneal, or fallopian cancer isplatinum-sensitive.
 3. The method of claim 1, wherein the individual hasreceived a prior platinum-based chemotherapy and has a treatment freeinterval of more than about 12 months since the completion of theplatinum-based chemotherapy.
 4. The method of claim 1, wherein thecomposition comprising nanoparticles comprising a taxane and a carrierprotein is administered alone.
 5. The method of claim 1, wherein thetaxane is paclitaxel.
 6. The method of claim 1, wherein the carrierprotein is albumin.
 7. The method of claim 1, wherein the nanoparticlesin the composition have an average or mean diameter of less than about200 nm.
 8. The method of claim 7, wherein the composition comprisingnanoparticles comprising a taxane and a carrier protein isNab-paclitaxel.
 9. The method of claim 1, wherein the individual hasreceived a prior chemotherapy and has a treatment free interval for moreabout 6 months prior to the initiation of the treatment.
 10. The methodof claim 1, wherein the individual does not show a symptom ofhypersensitivity prior to the initiation of the treatment.
 11. Themethod of claim 1, wherein the individual does not show a symptomresulting from the recurrent cancer upon completion of the treatment.12. The method of claim 1, wherein the individual has a reduced CA-125level upon completion of the treatment.
 13. A method of treating arecurrent ovarian, peritoneal, or fallopian tube cancer in anindividual, comprising administering to the individual: a) an effectiveamount of a composition comprising nanoparticles comprising a taxane anda carrier protein, and b) an effective amount of a platinum-based agent.14. The method of claim 13, wherein the composition comprisingnanoparticles and the platinum-based agent are concurrentlyadministered.
 15. The method of claim 13, wherein the platinum-basedagent is carboplatin.
 16. The method of claim 13, wherein the individualhas received a prior platinum-based chemotherapy and has a treatmentfree interval of more than about 12 months since the completion of theplatinum-based chemotherapy.
 17. The method of claim 13, wherein thetaxane is paclitaxel.
 18. The method of claim 13, wherein the carrierprotein is albumin.
 19. The method of claim 13, wherein thenanoparticles in the composition have an average or mean diameter ofless than about 200 nm.
 20. The method of claim 19, wherein thecomposition comprising nanoparticles comprising a taxane and a carrierprotein is Nab-paclitaxel. 21-24. (canceled)